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1. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Author

Elinor Sawyer, Rebecca Roylance, Christos Petridis, Mark N Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine-Anne Perkins, Cheryl Gillett, Richard Houlston, Gillian Ross, Paolo De Ieso, Melissa C Southey, John L Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A Fasching, Sebastian M Jud, Arif B Ekici, Matthias W Beckmann, Michael J Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-Peter Fischer, Yon-Dschun Ko, GENICA Network, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, KConFab Investigators, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona A McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Jonine Figueroa, Stephen J Chanock, Mark E Sherman, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Carolien H M van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Mitul Shah, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J Couch, Emily Hallberg, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel C Tessier, Daniel Vincent, Francois Bacot, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M Dunning, Per Hall, Doug Easton, Paul Pharoah, Marjanka K Schmidt, Ian Tomlinson, and Montserrat Garcia-Closas

Subjects
Genetics, QH426-470
Abstract

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P

Published
2014
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2. MicroRNA related polymorphisms and breast cancer risk.

Author

Sofia Khan, Dario Greco, Kyriaki Michailidou, Roger L Milne, Taru A Muranen, Tuomas Heikkinen, Kirsimari Aaltonen, Joe Dennis, Manjeet K Bolla, Jianjun Liu, Per Hall, Astrid Irwanto, Keith Humphreys, Jingmei Li, Kamila Czene, Jenny Chang-Claude, Rebecca Hein, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Olivia Fletcher, Julian Peto, Isabel dos Santos Silva, Nichola Johnson, Lorna Gibson, Zoe Aitken, John L Hopper, Helen Tsimiklis, Minh Bui, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Carmel Apicella, Jennifer Stone, Quinten Waisfisz, Hanne Meijers-Heijboer, Muriel A Adank, Rob B van der Luijt, Alfons Meindl, Rita K Schmutzler, Bertram Müller-Myhsok, Peter Lichtner, Clare Turnbull, Nazneen Rahman, Stephen J Chanock, David J Hunter, Angela Cox, Simon S Cross, Malcolm W R Reed, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Frans B Hogervorst, Peter A Fasching, Michael G Schrauder, Arif B Ekici, Matthias W Beckmann, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Pilar M Zamora, Jose I A Perez, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Robert Luben, Judith Brown, Fergus J Couch, Xianshu Wang, Celine Vachon, Janet E Olson, Diether Lambrechts, Matthieu Moisse, Robert Paridaens, Marie-Rose Christiaens, Pascal Guénel, Thérèse Truong, Pierre Laurent-Puig, Claire Mulot, Frederick Marme, Barbara Burwinkel, Andreas Schneeweiss, Christof Sohn, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Irene L Andrulis, Julia A Knight, Sandrine Tchatchou, Anna Marie Mulligan, Thilo Dörk, Natalia V Bogdanova, Natalia N Antonenkova, Hoda Anton-Culver, Hatef Darabi, Mikael Eriksson, Montserrat Garcia-Closas, Jonine Figueroa, Jolanta Lissowska, Louise Brinton, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J van Asperen, Vessela N Kristensen, kConFab Investigators, Australian Ovarian Cancer Study Group, Susan Slager, Amanda E Toland, Christine B Ambrosone, Drakoulis Yannoukakos, Annika Lindblom, Sara Margolin, Paolo Radice, Paolo Peterlongo, Monica Barile, Paolo Mariani, Maartje J Hooning, John W M Martens, J Margriet Collée, Agnes Jager, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Graham G Giles, Catriona McLean, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, GENICA Network, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Arto Mannermaa, Ute Hamann, Georgia Chenevix-Trench, Carl Blomqvist, Kristiina Aittomäki, Douglas F Easton, and Heli Nevanlinna

Subjects
Medicine, Science
Abstract

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.

Published
2014
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3. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Author

Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M Sinilnikova, Vernon S Pankratz, Xianshu Wang, Ronald C Eldridge, Daniel C Tessier, Daniel Vincent, Francois Bacot, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, KConFab Investigators, Paolo Peterlongo, Rita K Schmutzler, Katherine L Nathanson, Marion Piedmonte, Christian F Singer, Mads Thomassen, Ontario Cancer Genetics Network, Thomas v O Hansen, Susan L Neuhausen, Ignacio Blanco, Mark H Greene, Judith Garber, Jeffrey N Weitzel, Irene L Andrulis, David E Goldgar, Emma D'Andrea, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Elizabeth J van Rensburg, Adalgeir Arason, Gad Rennert, Ans M W van den Ouweland, Annemarie H van der Hout, Carolien M Kets, Cora M Aalfs, Juul T Wijnen, Margreet G E M Ausems, HEBON, EMBRACE, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E Porteous, Francesca Damiola, GEMO Study Collaborators, Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L Mai, Javier Benitez, Melissa C Southey, Marjanka K Schmidt, Peter A Fasching, Julian Peto, Manjeet K Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J Sawyer, Barbara Burwinkel, Pascal Guénel, Stig E Bojesen, Roger L Milne, Hermann Brenner, Magdalena Lochmann, GENICA Network, Kristiina Aittomäki, Thilo Dörk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G Giles, Christopher A Haiman, Robert Winqvist, Peter Devillee, Montserrat García-Closas, Nils Schoof, Maartje J Hooning, Angela Cox, Paul D P Pharoah, Anna Jakubowska, Nick Orr, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, and Kenneth Offit

Subjects
Genetics, QH426-470
Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013
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4. Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors.

Author

Stefan Nickels, Thérèse Truong, Rebecca Hein, Kristen Stevens, Katharina Buck, Sabine Behrens, Ursula Eilber, Martina Schmidt, Lothar Häberle, Alina Vrieling, Mia Gaudet, Jonine Figueroa, Nils Schoof, Amanda B Spurdle, Anja Rudolph, Peter A Fasching, John L Hopper, Enes Makalic, Daniel F Schmidt, Melissa C Southey, Matthias W Beckmann, Arif B Ekici, Olivia Fletcher, Lorna Gibson, Isabel dos Santos Silva, Julian Peto, Manjeet K Humphreys, Jean Wang, Emilie Cordina-Duverger, Florence Menegaux, Børge G Nordestgaard, Stig E Bojesen, Charlotte Lanng, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Hiltrud Brauch, Thomas Brüning, Volker Harth, Genica Network, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, kConFab, AOCS Management Group, Diether Lambrechts, Dominiek Smeets, Patrick Neven, Robert Paridaens, Dieter Flesch-Janys, Nadia Obi, Shan Wang-Gohrke, Fergus J Couch, Janet E Olson, Celine M Vachon, Graham G Giles, Gianluca Severi, Laura Baglietto, Kenneth Offit, Esther M John, Alexander Miron, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Stephen J Chanock, Jolanta Lissowska, Jianjun Liu, Angela Cox, Helen Cramp, Dan Connley, Sabapathy Balasubramanian, Alison M Dunning, Mitul Shah, Amy Trentham-Dietz, Polly Newcomb, Linda Titus, Kathleen Egan, Elizabeth K Cahoon, Preetha Rajaraman, Alice J Sigurdson, Michele M Doody, Pascal Guénel, Paul D P Pharoah, Marjanka K Schmidt, Per Hall, Doug F Easton, Montserrat Garcia-Closas, Roger L Milne, and Jenny Chang-Claude

Subjects
Genetics, QH426-470
Abstract

Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of

Published
2013
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5. Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Author

Rebecca Hein, Melanie Maranian, John L Hopper, Miroslaw K Kapuscinski, Melissa C Southey, Daniel J Park, Marjanka K Schmidt, Annegien Broeks, Frans B L Hogervorst, H Bas Bueno-de-Mesquita, Kenneth R Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A Fasching, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, M Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R Bartram, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, GENICA Network, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Iosif V Zalutsky, Natalia N Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, Kconfab Investigators, AOCS Group, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Graham G Giles, Laura Baglietto, Catriona A McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Jonine D Figueroa, Montserrat García-Closas, Jolanta Lissowska, Mark E Sherman, Maartje Hooning, John W M Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W Brock, Simon S Cross, Malcolm W R Reed, Shahana Ahmed, Maya Ghoussaini, Paul D P Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A Newcomb, Linda Titus, Kathleen M Egan, Georgia Chenevix-Trench, Antonis C Antoniou, Manjeet K Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F Easton, and Alison M Dunning

Subjects
Medicine, Science
Abstract

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

Published
2012
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6. Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Author

Tomas Kirchhoff, Mia M Gaudet, Antonis C Antoniou, Lesley McGuffog, Manjeet K Humphreys, Alison M Dunning, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Thilo Dork, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Fergus J Couch, Janet Olson, Celine Vachon, Xianshu Wang, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W R Reed, Barbara Burwinkel, Alfons Meindl, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, GENICA Network, Annegien Broeks, Marjanka K Schmidt, Laura J Van 't Veer, Linde M Braaf, Nichola Johnson, Olivia Fletcher, Lorna Gibson, Julian Peto, Clare Turnbull, Sheila Seal, Anthony Renwick, Nazneen Rahman, Pei-Ei Wu, Jyh-Cherng Yu, Chia-Ni Hsiung, Chen-Yang Shen, Melissa C Southey, John L Hopper, Fleur Hammet, Thijs Van Dorpe, Anne-Sophie Dieudonne, Sigrid Hatse, Diether Lambrechts, Irene L Andrulis, Natalia Bogdanova, Natalia Antonenkova, Juri I Rogov, Daria Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Christi J van Asperen, Robert A E M Tollenaar, Maartje J Hooning, Peter Devilee, Sara Margolin, Annika Lindblom, Roger L Milne, José Ignacio Arias, M Pilar Zamora, Javier Benítez, Gianluca Severi, Laura Baglietto, Graham G Giles, kConFab, AOCS Study Group, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Helene Holland, Sue Healey, Shan Wang-Gohrke, Jenny Chang-Claude, Arto Mannermaa, Veli-Matti Kosma, Jaana Kauppinen, Vesa Kataja, Bjarni A Agnarsson, Maria A Caligo, Andrew K Godwin, Heli Nevanlinna, Tuomas Heikkinen, Zachary Fredericksen, Noralane Lindor, Katherine L Nathanson, Susan M Domchek, SWE-BRCA, Niklas Loman, Per Karlsson, Marie Stenmark Askmalm, Beatrice Melin, Anna von Wachenfeldt, HEBON, Frans B L Hogervorst, Martijn Verheus, Matti A Rookus, Caroline Seynaeve, Rogier A Oldenburg, Marjolijn J Ligtenberg, Margreet G E M Ausems, Cora M Aalfs, Hans J P Gille, Juul T Wijnen, Encarna B Gómez García, EMBRACE, Susan Peock, Margaret Cook, Clare T Oliver, Debra Frost, Craig Luccarini, Gabriella Pichert, Rosemarie Davidson, Carol Chu, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Shirley Hodgson, D Gareth Evans, Rosalind Eeles, Bert Gold, Paul D P Pharoah, Kenneth Offit, Georgia Chenevix-Trench, Douglas F Easton, and BCAC/CIMBA

Subjects
Medicine, Science
Abstract

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p =

Published
2012
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7. Investigation of gene‐environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

Author

Rudolph, Anja, Milne, Roger L, Truong, Thérèse, Knight, Julia A, Seibold, Petra, Flesch‐Janys, Dieter, Behrens, Sabine, Eilber, Ursula, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Dunning, Alison M, Shah, Mitul, Munday, Hannah R, Darabi, Hatef, Eriksson, Mikael, Brand, Judith S, Olson, Janet, Vachon, Celine M, Hallberg, Emily, Castelao, J Esteban, Carracedo, Angel, Torres, Maria, Li, Jingmei, Humphreys, Keith, Cordina‐Duverger, Emilie, Menegaux, Florence, Flyger, Henrik, Nordestgaard, Børge G, Nielsen, Sune F, Yesilyurt, Betul T, Floris, Giuseppe, Leunen, Karin, Engelhardt, Ellen G, Broeks, Annegien, Rutgers, Emiel J, Glendon, Gord, Mulligan, Anna Marie, Cross, Simon, Reed, Malcolm, Gonzalez‐Neira, Anna, Perez, José Ignacio Arias, Provenzano, Elena, Apicella, Carmel, Southey, Melissa C, Spurdle, Amanda, Investigators, kConFab, Group, AOCS, Häberle, Lothar, Beckmann, Matthias W, Ekici, Arif B, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, McLean, Catriona, Baglietto, Laura, Chanock, Stephen J, Lissowska, Jolanta, Sherman, Mark E, Brüning, Thomas, Hamann, Ute, Ko, Yon‐Dschun, Orr, Nick, Schoemaker, Minouk, Ashworth, Alan, Kosma, Veli‐Matti, Kataja, Vesa, Hartikainen, Jaana M, Mannermaa, Arto, Swerdlow, Anthony, GENICA‐Network, Giles, Graham G, Brenner, Hermann, Fasching, Peter A, Chenevix‐Trench, Georgia, Hopper, John, Benítez, Javier, Cox, Angela, Andrulis, Irene L, Lambrechts, Diether, Gago‐Dominguez, Manuela, Couch, Fergus, Czene, Kamila, Bojesen, Stig E, Easton, Doug F, Schmidt, Marjanka K, Guénel, Pascal, Hall, Per, Pharoah, Paul DP, Garcia‐Closas, Montserrat, and Chang‐Claude, Jenny

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Aging, Prevention, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Female, Gene-Environment Interaction, Genetic Loci, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, gene-environment interaction, breast cancer, risk factor, genetic susceptibility, kConFab Investigators, AOCS Group, GENICA-Network, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint )

Published
2015

8. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Author

Painter, Jodie N, O'Mara, Tracy A, Batra, Jyotsna, Cheng, Timothy, Lose, Felicity A, Dennis, Joe, Michailidou, Kyriaki, Tyrer, Jonathan P, Ahmed, Shahana, Ferguson, Kaltin, Healey, Catherine S, Kaufmann, Susanne, Hillman, Kristine M, Walpole, Carina, Moya, Leire, Pollock, Pamela, Jones, Angela, Howarth, Kimberley, Martin, Lynn, Gorman, Maggie, Hodgson, Shirley, National Study of Endometrial Cancer Genetics Group (NSECG), CHIBCHA Consortium, De Polanco, Ma Magdalena Echeverry, Sans, Monica, Carracedo, Angel, Castellvi-Bel, Sergi, Rojas-Martinez, Augusto, Santos, Erika, Teixeira, Manuel R, Carvajal-Carmona, Luis, Shu, Xiao-Ou, Long, Jirong, Zheng, Wei, Xiang, Yong-Bing, Australian National Endometrial Cancer Study Group (ANECS), Montgomery, Grant W, Webb, Penelope M, Scott, Rodney J, McEvoy, Mark, Attia, John, Holliday, Elizabeth, Martin, Nicholas G, Nyholt, Dale R, Henders, Anjali K, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Renner, Stefan P, Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Lambrechts, Diether, Coenegrachts, Lieve, Schrauwen, Stefanie, Amant, Frederic, Winterhoff, Boris, Dowdy, Sean C, Goode, Ellen L, Teoman, Attila, Salvesen, Helga B, Trovik, Jone, Njolstad, Tormund S, Werner, Henrica MJ, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Tzortzatos, Gerasimos, Mints, Miriam, Tham, Emma, RENDOCAS, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Jingmei, Hopper, John L, Southey, Melissa C, Australian Ovarian Cancer Study (AOCS), Ekici, Arif B, Ruebner, Matthias, Johnson, Nicola, Peto, Julian, Burwinkel, Barbara, Marme, Frederik, Brenner, Hermann, Dieffenbach, Aida K, Meindl, Alfons, Brauch, Hiltrud, GENICA Network, Lindblom, Annika, Depreeuw, Jeroen, Moisse, Matthieu, Chang-Claude, Jenny, Rudolph, Anja, Couch, Fergus J, Olson, Janet E, Giles, Graham G, Bruinsma, Fiona, and Cunningham, Julie M

Subjects
National Study of Endometrial Cancer Genetics Group, CHIBCHA Consortium, Australian National Endometrial Cancer Study Group, RENDOCAS, Australian Ovarian Cancer Study, GENICA Network, Cell Line, Tumor, Humans, Endometrial Neoplasms, RNA, Messenger, Risk Factors, Case-Control Studies, Chromosome Mapping, Computational Biology, Epigenesis, Genetic, Genotype, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Databases, Genetic, European Continental Ancestry Group, Female, Hepatocyte Nuclear Factor 1-beta, Promoter Regions, Genetic, Genetic Variation, Genome-Wide Association Study, Genetic Loci, Cell Line, Tumor, Databases, Genetic, Epigenesis, Polymorphism, Single Nucleotide, Promoter Regions, RNA, Messenger, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

Published
2015

9. Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author

Carvajal-Carmona, Luis G, O’Mara, Tracy A, Painter, Jodie N, Lose, Felicity A, Dennis, Joe, Michailidou, Kyriaki, Tyrer, Jonathan P, Ahmed, Shahana, Ferguson, Kaltin, Healey, Catherine S, Pooley, Karen, Beesley, Jonathan, Cheng, Timothy, Jones, Angela, Howarth, Kimberley, Martin, Lynn, Gorman, Maggie, Hodgson, Shirley, National Study of Endometrial Cancer Genetics Group (NSECG), The Australian National Endometrial Cancer Study Group (ANECS), Wentzensen, Nicholas, Fasching, Peter A, Hein, Alexander, Beckmann, Matthias W, Renner, Stefan P, Dörk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Lambrechts, Diether, Coenegrachts, Lieve, Schrauwen, Stefanie, Amant, Frederic, Winterhoff, Boris, Dowdy, Sean C, Goode, Ellen L, Teoman, Attila, Salvesen, Helga B, Trovik, Jone, Njolstad, Tormund S, Werner, Henrica MJ, Scott, Rodney J, Ashton, Katie, Proietto, Tony, Otton, Geoffrey, Wersäll, Ofra, Mints, Miriam, Tham, Emma, RENDOCAS, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Jingmei, Hopper, John L, Southey, Melissa C, Australian Ovarian Cancer Study (AOCS), Ekici, Arif B, Ruebner, Matthias, Johnson, Nichola, Peto, Julian, Burwinkel, Barbara, Marme, Frederik, Brenner, Hermann, Dieffenbach, Aida K, Meindl, Alfons, Brauch, Hiltrud, The GENICA Network, Lindblom, Annika, Depreeuw, Jeroen, Moisse, Matthieu, Chang-Claude, Jenny, Rudolph, Anja, Couch, Fergus J, Olson, Janet E, Giles, Graham G, Bruinsma, Fiona, Cunningham, Julie M, Fridley, Brooke L, Børresen-Dale, Anne-Lise, Kristensen, Vessela N, Cox, Angela, Swerdlow, Anthony J, Orr, Nicholas, Bolla, Manjeet K, Wang, Qin, Weber, Rachel Palmieri, Chen, Zhihua, Shah, Mitul, Pharoah, Paul DP, Dunning, Alison M, Tomlinson, Ian, Easton, Douglas F, Spurdle, Amanda B, and Thompson, Deborah J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Genetic Testing, Human Genome, Prevention, Cancer, Uterine Cancer, 2.1 Biological and endogenous factors, Aetiology, Chromosomes, Human, Pair 5, Databases, Nucleic Acid, Female, Gene Expression Regulation, Neoplastic, Genetic Loci, Haplotypes, Humans, Membrane Proteins, Models, Genetic, Neoplasm Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Factors, Telomerase, National Study of Endometrial Cancer Genetics Group, Australian National Endometrial Cancer Study Group, RENDOCAS, Australian Ovarian Cancer Study, GENICA Network, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

Published
2015

10. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Author

Lin, Wei-Yu, Camp, Nicola J, Ghoussaini, Maya, Beesley, Jonathan, Michailidou, Kyriaki, Hopper, John L, Apicella, Carmel, Southey, Melissa C, Stone, Jennifer, Schmidt, Marjanka K, Broeks, Annegien, Van't Veer, Laura J, Th Rutgers, Emiel J, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Sawyer, Elinor J, Cheng, Timothy, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marmé, Frederik, Surowy, Harald M, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Mulot, Claire, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Arias Perez, Jose Ignacio, Menéndez, Primitiva, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Alvarez, Nuria, Herrero, Daniel, Anton-Culver, Hoda, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K, Müller-Myhsok, Bertram, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, GENICA Network, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Horio, Akiyo, Bogdanova, Natalia V, Antonenkova, Natalia N, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O, Neven, Patrick, Wauters, Els, Wildiers, Hans, Lambrechts, Diether, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, and Flesch-Janys, Dieter

Subjects
GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Chromosomes, Human, Pair 2, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Proteins, Case-Control Studies, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Caspase 8, CASP8 and FADD-Like Apoptosis Regulating Protein, Genome-Wide Association Study, Genotyping Techniques, Chromosomes, Human, Pair 2, Polymorphism, Single Nucleotide, Prevention, Genetics, Human Genome, Breast Cancer, Cancer, Biotechnology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

Published
2015

11. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

Author

Purrington, Kristen S, Slettedahl, Seth, Bolla, Manjeet K, Michailidou, Kyriaki, Czene, Kamila, Nevanlinna, Heli, Bojesen, Stig E, Andrulis, Irene L, Cox, Angela, Hall, Per, Carpenter, Jane, Yannoukakos, Drakoulis, Haiman, Christopher A, Fasching, Peter A, Mannermaa, Arto, Winqvist, Robert, Brenner, Hermann, Lindblom, Annika, Chenevix-Trench, Georgia, Benitez, Javier, Swerdlow, Anthony, Kristensen, Vessela, Guénel, Pascal, Meindl, Alfons, Darabi, Hatef, Eriksson, Mikael, Fagerholm, Rainer, Aittomäki, Kristiina, Blomqvist, Carl, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Wang, Xianshu, Olswold, Curtis, Olson, Janet E, Mulligan, Anna Marie, Knight, Julia A, Tchatchou, Sandrine, Reed, Malcolm WR, Cross, Simon S, Liu, Jianjun, Li, Jingmei, Humphreys, Keith, Clarke, Christine, Scott, Rodney, ABCTB Investigators, Fostira, Florentia, Fountzilas, George, Konstantopoulou, Irene, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Ekici, Arif B, Hartmann, Arndt, Beckmann, Matthias W, Hartikainen, Jaana M, Kosma, Veli-Matti, Kataja, Vesa, Jukkola-Vuorinen, Arja, Pylkäs, Katri, Kauppila, Saila, Dieffenbach, Aida Karina, Stegmaier, Christa, Arndt, Volker, Margolin, Sara, Australian Ovarian Cancer Study Group, kConFab Investigators, Balleine, Rosemary, Arias Perez, Jose Ignacio, Pilar Zamora, M, Menéndez, Primitiva, Ashworth, Alan, Jones, Michael, Orr, Nick, Arveux, Patrick, Kerbrat, Pierre, Truong, Thérèse, Bugert, Peter, Toland, Amanda E, Ambrosone, Christine B, Labrèche, France, Goldberg, Mark S, Dumont, Martine, Ziogas, Argyrios, Lee, Eunjung, Dite, Gillian S, Apicella, Carmel, Southey, Melissa C, Long, Jirong, Shrubsole, Martha, Deming-Halverson, Sandra, Ficarazzi, Filomena, Barile, Monica, Peterlongo, Paolo, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Tollenaar, Robert AEM, Seynaeve, Caroline, GENICA Network, and Brüning, Thomas

Subjects
ABCTB Investigators, Australian Ovarian Cancer Study Group, kConFab Investigators, GENICA Network, Humans, Breast Neoplasms, Carrier Proteins, Tumor Suppressor Proteins, Neoplasm Staging, Risk Factors, Case-Control Studies, Haplotypes, Polymorphism, Single Nucleotide, Female, Receptor, Fibroblast Growth Factor, Type 2, Genetic Variation, Genetics, Breast Cancer, Prevention, Human Genome, Cancer, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

Published
2014

12. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer.

Author

Purrington, Kristen S, Slager, Susan, Eccles, Diana, Yannoukakos, Drakoulis, Fasching, Peter A, Miron, Penelope, Carpenter, Jane, Chang-Claude, Jenny, Martin, Nicholas G, Montgomery, Grant W, Kristensen, Vessela, Anton-Culver, Hoda, Goodfellow, Paul, Tapper, William J, Rafiq, Sajjad, Gerty, Susan M, Durcan, Lorraine, Konstantopoulou, Irene, Fostira, Florentia, Vratimos, Athanassios, Apostolou, Paraskevi, Konstanta, Irene, Kotoula, Vassiliki, Lakis, Sotiris, Dimopoulos, Meletios A, Skarlos, Dimosthenis, Pectasides, Dimitrios, Fountzilas, George, Beckmann, Matthias W, Hein, Alexander, Ruebner, Matthias, Ekici, Arif B, Hartmann, Arndt, Schulz-Wendtland, Ruediger, Renner, Stefan P, Janni, Wolfgang, Rack, Brigitte, Scholz, Christoph, Neugebauer, Julia, Andergassen, Ulrich, Lux, Michael P, Haeberle, Lothar, Clarke, Christine, Pathmanathan, Nirmala, Rudolph, Anja, Flesch-Janys, Dieter, Nickels, Stefan, Olson, Janet E, Ingle, James N, Olswold, Curtis, Slettedahl, Seth, Eckel-Passow, Jeanette E, Anderson, S Keith, Visscher, Daniel W, Cafourek, Victoria L, Sicotte, Hugues, Prodduturi, Naresh, Weiderpass, Elisabete, Bernstein, Leslie, Ziogas, Argyrios, Ivanovich, Jennifer, Giles, Graham G, Baglietto, Laura, Southey, Melissa, Kosma, Veli-Matti, Fischer, Hans-Peter, GENICA Network, Reed, Malcom WR, Cross, Simon S, Deming-Halverson, Sandra, Shrubsole, Martha, Cai, Qiuyin, Shu, Xiao-Ou, Daly, Mary, Weaver, Joellen, Ross, Eric, Klemp, Jennifer, Sharma, Priyanka, Torres, Diana, Rüdiger, Thomas, Wölfing, Heidrun, Ulmer, Hans-Ulrich, Försti, Asta, Khoury, Thaer, Kumar, Shicha, Pilarski, Robert, Shapiro, Charles L, Greco, Dario, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Irwanto, Astrid, Liu, Jianjun, Pankratz, Vernon Shane, Wang, Xianshu, Severi, Gianluca, Mannermaa, Arto, Easton, Douglas, Hall, Per, and Brauch, Hiltrud

Subjects
GENICA Network, Chromosomes, Human, Pair 19, Humans, Genetic Predisposition to Disease, Estrogen Receptor alpha, Case-Control Studies, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Genome-Wide Association Study, Young Adult, Triple Negative Breast Neoplasms, Prevention, Genetics, Cancer, Breast Cancer, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Chromosomes, Human, Pair 19, Polymorphism, Single Nucleotide, and over, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

Published
2014

13. Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

Author

Meyer, Kerstin B, O'Reilly, Martin, Michailidou, Kyriaki, Carlebur, Saskia, Edwards, Stacey L, French, Juliet D, Prathalingham, Radhika, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, de Santiago, Ines, Hopper, John L, Tsimiklis, Helen, Apicella, Carmel, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Van 't Veer, Laura J, Hogervorst, Frans B, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Lux, Michael P, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos Santos Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Zamora, M Pilar, Arias, Jose I, Benitez, Javier, Neuhausen, Susan, Anton-Culver, Hoda, Ziogas, Argyrios, Dur, Christina C, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K, Engel, Christoph, Ditsch, Nina, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, GENICA Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Yatabe, Yasushi, Dörk, Thilo, Helbig, Sonja, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Chenevix-Trench, Georgia, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O, Lambrechts, Diether, Thienpont, Bernard, Christiaens, Marie-Rose, Smeets, Ann, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, and Radice, Paolo

Subjects
GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Cell Line, Tumor, Humans, Breast Neoplasms, Case-Control Studies, Chromatin Immunoprecipitation, Chromosome Mapping, Gene Expression Regulation, Neoplastic, RNA Interference, Binding Sites, Protein Binding, Haplotypes, Alleles, Female, E2F1 Transcription Factor, Receptor, Fibroblast Growth Factor, Type 2, Hepatocyte Nuclear Factor 3-alpha, Promoter Regions, Genetic, Genetic Loci, Position-Specific Scoring Matrices, Genetic Association Studies, Asian People, White People, Black People, Cancer, Human Genome, Breast Cancer, Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.

Published
2013

14. A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication

Author

Hein, Rebecca, Flesch-Janys, Dieter, Dahmen, Norbert, Beckmann, Lars, Lindström, Sara, Schoof, Nils, Czene, Kamila, Mittelstraß, Kirstin, Illig, Thomas, Seibold, Petra, Behrens, Sabine, Humphreys, Keith, Li, Jingmei, Liu, Jianjun, Olson, Janet E, Wang, Xianshu, Hankinson, Susan E, Truong, Thérèse, Menegaux, Florence, dos Santos Silva, Isabel, Johnson, Nichola, The GENICA Network, Chen, Shou-Tung, Yu, Jyh-Cherng, Ziogas, Argyrios, Kataja, Vesa, Kosma, Veli-Matti, Mannermaa, Arto, Anton-Culver, Hoda, Shen, Chen-Yang, Brauch, Hiltrud, Peto, Julian, Guénel, Pascal, Kraft, Peter, Couch, Fergus J, Easton, Douglas F, Hall, Per, and Chang-Claude, Jenny

Subjects
Cancer, Aging, Prevention, Breast Cancer, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Carcinoma, Ductal, Breast, Carcinoma, Lobular, Case-Control Studies, Chromosomes, Human, Estrogen Replacement Therapy, Estrogens, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Postmenopause, Progestins, Risk Factors, Sequence Analysis, DNA, Postmenopausal breast cancer risk, Menopausal hormone therapy, Polymorphisms, Gene-environment interaction, Genome-wide association study, Case-only study, GENICA Network, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values

Published
2013

15. Evidence of Gene�Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Author

Nickels, Stefan, Truong, Thérèse, Hein, Rebecca, Stevens, Kristen, Buck, Katharina, Behrens, Sabine, Eilber, Ursula, Schmidt, Martina, Häberle, Lothar, Vrieling, Alina, Gaudet, Mia, Figueroa, Jonine, Schoof, Nils, Spurdle, Amanda B, Rudolph, Anja, Fasching, Peter A, Hopper, John L, Makalic, Enes, Schmidt, Daniel F, Southey, Melissa C, Beckmann, Matthias W, Ekici, Arif B, Fletcher, Olivia, Gibson, Lorna, dos Santos Silva, Isabel, Peto, Julian, Humphreys, Manjeet K, Wang, Jean, Cordina-Duverger, Emilie, Menegaux, Florence, Nordestgaard, Børge G, Bojesen, Stig E, Lanng, Charlotte, Anton-Culver, Hoda, Ziogas, Argyrios, Bernstein, Leslie, Clarke, Christina A, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Harth, Volker, GENICA Network, The, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, kConFab, The, Group, AOCS Management, Lambrechts, Diether, Smeets, Dominiek, Neven, Patrick, Paridaens, Robert, Flesch-Janys, Dieter, Obi, Nadia, Wang-Gohrke, Shan, Couch, Fergus J, Olson, Janet E, Vachon, Celine M, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, Offit, Kenneth, John, Esther M, Miron, Alexander, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Chanock, Stephen J, Lissowska, Jolanta, Liu, Jianjun, Cox, Angela, Cramp, Helen, Connley, Dan, Balasubramanian, Sabapathy, Dunning, Alison M, Shah, Mitul, Trentham-Dietz, Amy, Newcomb, Polly, Titus, Linda, Egan, Kathleen, Cahoon, Elizabeth K, Rajaraman, Preetha, Sigurdson, Alice J, Doody, Michele M, Guénel, Pascal, Pharoah, Paul D. P, Schmidt, Marjanka K, Hall, Per, Easton, Doug F, Garcia-Closas, Montserrat, Milne, Roger L, Chang-Claude, Jenny, and Horwitz, Marshall S

Subjects
Genome-Wide Association, Mammographic Density, 14q24.1 Rad51l1, Hormone-Therapy, Pooled Analysis, Tumor Subtypes, Variants, Consortium, Fgfr2, Women
Published
2013

16. Genome-wide association analysis identifies three new breast cancer susceptibility loci.

Author

Ghoussaini, Maya, Fletcher, Olivia, Michailidou, Kyriaki, Turnbull, Clare, Schmidt, Marjanka K, Dicks, Ed, Dennis, Joe, Wang, Qin, Humphreys, Manjeet K, Luccarini, Craig, Baynes, Caroline, Conroy, Don, Maranian, Melanie, Ahmed, Shahana, Driver, Kristy, Johnson, Nichola, Orr, Nicholas, dos Santos Silva, Isabel, Waisfisz, Quinten, Meijers-Heijboer, Hanne, Uitterlinden, Andre G, Rivadeneira, Fernando, Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer (HEBON), Hall, Per, Czene, Kamila, Irwanto, Astrid, Liu, Jianjun, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Meindl, Alfons, Schmutzler, Rita K, Müller-Myhsok, Bertram, Lichtner, Peter, Chang-Claude, Jenny, Hein, Rebecca, Nickels, Stefan, Flesch-Janys, Dieter, Tsimiklis, Helen, Makalic, Enes, Schmidt, Daniel, Bui, Minh, Hopper, John L, Apicella, Carmel, Park, Daniel J, Southey, Melissa, Hunter, David J, Chanock, Stephen J, Broeks, Annegien, Verhoef, Senno, Hogervorst, Frans BL, Fasching, Peter A, Lux, Michael P, Beckmann, Matthias W, Ekici, Arif B, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Cordina-Duverger, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Alonso, M Rosario, González-Neira, Anna, Benítez, Javier, Anton-Culver, Hoda, Ziogas, Argyrios, Bernstein, Leslie, Dur, Christina Clarke, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Familial Breast Cancer Study (FBCS), Justenhoven, Christina, Brauch, Hiltrud, Brüning, Thomas, Gene Environment Interaction of Breast Cancer in Germany (GENICA) Network, Wang-Gohrke, Shan, Eilber, Ursula, Dörk, Thilo, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Bogdanova, Natalia V, Antonenkova, Natalia N, Rogov, Yuri I, Karstens, Johann H, Bermisheva, Marina, Prokofieva, Darya, and Khusnutdinova, Elza

Subjects
Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer, Familial Breast Cancer Study, Gene Environment Interaction of Breast Cancer in Germany (GENICA) Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Logistic Models, Polymorphism, Single Nucleotide, Principal Component Analysis, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genetic Loci, Chromosomes, Human, Pair 12, Pair 21, Polymorphism, Single Nucleotide, Genetics, Human Genome, Aging, Prevention, Cancer, Breast Cancer, 2.1 Biological and endogenous factors, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Published
2012

17. Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Author

Kirchhoff, Tomas, Gaudet, Mia M, Antoniou, Antonis C, McGuffog, Lesley, Humphreys, Manjeet K, Dunning, Alison M, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Ahn, Sei-Hyun, Dork, Thilo, Schürmann, Peter, Karstens, Johann H, Hillemanns, Peter, Couch, Fergus J, Olson, Janet, Vachon, Celine, Wang, Xianshu, Cox, Angela, Brock, Ian, Elliott, Graeme, Reed, Malcolm WR, Burwinkel, Barbara, Meindl, Alfons, Brauch, Hiltrud, Hamann, Ute, Ko, Yon-Dschun, GENICA Network, Broeks, Annegien, Schmidt, Marjanka K, Van 't Veer, Laura J, Braaf, Linde M, Johnson, Nichola, Fletcher, Olivia, Gibson, Lorna, Peto, Julian, Turnbull, Clare, Seal, Sheila, Renwick, Anthony, Rahman, Nazneen, Wu, Pei-Ei, Yu, Jyh-Cherng, Hsiung, Chia-Ni, Shen, Chen-Yang, Southey, Melissa C, Hopper, John L, Hammet, Fleur, Van Dorpe, Thijs, Dieudonne, Anne-Sophie, Hatse, Sigrid, Lambrechts, Diether, Andrulis, Irene L, Bogdanova, Natalia, Antonenkova, Natalia, Rogov, Juri I, Prokofieva, Daria, Bermisheva, Marina, Khusnutdinova, Elza, van Asperen, Christi J, Tollenaar, Robert AEM, Hooning, Maartje J, Devilee, Peter, Margolin, Sara, Lindblom, Annika, Milne, Roger L, Arias, José Ignacio, Zamora, M Pilar, Benítez, Javier, Severi, Gianluca, Baglietto, Laura, Giles, Graham G, kConFab, AOCS Study Group, Spurdle, Amanda B, Beesley, Jonathan, Chen, Xiaoqing, Holland, Helene, Healey, Sue, Wang-Gohrke, Shan, Chang-Claude, Jenny, Mannermaa, Arto, Kosma, Veli-Matti, Kauppinen, Jaana, Kataja, Vesa, Agnarsson, Bjarni A, Caligo, Maria A, Godwin, Andrew K, Nevanlinna, Heli, Heikkinen, Tuomas, Fredericksen, Zachary, Lindor, Noralane, Nathanson, Katherine L, Domchek, Susan M, SWE-BRCA, Loman, Niklas, Karlsson, Per, and Stenmark Askmalm, Marie

Subjects
GENICA Network, kConFab, AOCS Study Group, SWE-BRCA, HEBON, EMBRACE, BCAC/CIMBA, Chromosomes, Human, Pair 6, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Receptors, Estrogen, Confidence Intervals, Proportional Hazards Models, Odds Ratio, Risk Factors, Heterozygote, Polymorphism, Single Nucleotide, Alleles, Middle Aged, Female, Genetic Association Studies, Chromosomes, Human, Pair 6, Polymorphism, Single Nucleotide, Receptors, Estrogen, General Science & Technology
Abstract

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p =

Published
2012

18. 7q21-rs6964587 and breast cancer risk: an extended case-control study by the Breast Cancer Association Consortium.

Author

Milne, Roger L, Lorenzo-Bermejo, Justo, Burwinkel, Barbara, Malats, Núria, Arias, Jose Ignacio, Zamora, M Pilar, Benítez, Javier, Humphreys, Manjeet K, García-Closas, Montserrat, Chanock, Stephen J, Lissowska, Jolanta, Sherman, Mark E, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomäki, Kristiina, Blomqvist, Carl, Anton-Culver, Hoda, Ziogas, Argyrios, Devilee, Peter, van Asperen, Christie J, Tollenaar, Rob AEM, Seynaeve, Caroline, Hall, Per, Czene, Kamila, Liu, Jianjun, Irwanto, Astrid K, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Nordestgaard, Børge G, Bojesen, Stig E, Flyger, Henrik, Margolin, Sara, Lindblom, Annika, Fasching, Peter A, Schulz-Wendtland, Ruediger, Ekici, Arif B, Beckmann, Matthias W, Wang-Gohrke, Shan, Shen, Chen-Yang, Yu, Jyh-Cherng, Hsu, Huan-Ming, Wu, Pei-Ei, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, English, Dallas R, Cox, Angela, Brock, Ian, Elliott, Graeme, Reed, Malcolm WR, Beesley, Jonathan, Chen, Xiaoqing, Investigators, Kconfab, AOCS Group, Fletcher, Olivia, Gibson, Lorna, dos Santos Silva, Isabel, Peto, Julian, Frank, Bernd, Heil, Joerg, Meindl, Alfons, Chang-Claude, Jenny, Hein, Rebecca, Vrieling, Alina, Flesch-Janys, Dieter, Southey, Melissa C, Smith, Letitia, Apicella, Carmel, Hopper, John L, Dunning, Alison M, Pooley, Karen A, Pharoah, Paul DP, Hamann, Ute, Pesch, Beate, Ko, Yon-Dschun, GENICA Network, Easton, Douglas F, and Chenevix-Trench, Georgia

Subjects
AOCS Group, GENICA Network, Chromosomes, Human, Pair 7, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Cytoskeletal Proteins, Logistic Models, Odds Ratio, Risk Factors, Case-Control Studies, Genes, Recessive, Polymorphism, Single Nucleotide, Alleles, Asian Continental Ancestry Group, European Continental Ancestry Group, Female, A Kinase Anchor Proteins, Chromosomes, Human, Pair 7, Genes, Recessive, Polymorphism, Single Nucleotide, Clinical Research, Cancer, Genetics, Breast Cancer, 2.1 Biological and endogenous factors, Genetics & Heredity, Biological Sciences, Medical and Health Sciences
Abstract

BackgroundUsing the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case-control studies.MethodsThe authors genotyped 14,843 invasive case patients and 19,852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression.ResultsFor white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p = 0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33,376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p = 0.001). The OR was greater at younger ages (p trend = 0.01).ConclusionThis may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.

Published
2011

19. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

Author

Lin, W.Y., Camp, N.J., Ghoussaini, M., Beesley, J., Michailidou, K., Hopper, J.L., Apicella, C., Southey, M.C., Stone, J., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Rutgers, E.J.T., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Bolla, M.K., Wang, Q., Dennis, J., Sawyer, E.J., Cheng, T., Tomlinson, I., Kerin, M.J., Miller, N., Marme, F., Surowy, H.M., Burwinkel, B., Guenel, P., Truong, T., Menegaux, F., Mulot, C., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrera, D., Anton-Culver, H., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Meindl, A., Lichtner, P., Schmutzler, R.K., Muller-Myhsok, B., Brauch, H., Bruning, T., Ko, Y.D., Tessier, D.C., Vincent, D., Bacot, F., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Khan, S., Matsuo, K., Ito, H., Iwata, H., Horio, A., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Neven, P., Wauters, E., Wildiers, H., Lambrechts, D., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Radice, P., Peterlongo, P., Manoukian, S., Bonanni, B., Couch, F.J., Wang, X.S., Vachon, C., Purrington, K., Giles, G.G., Milne, R.L., Mclean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Teo, S.H., Yip, C.H., Hassan, N., Vithana, E.N., Kristensen, V., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Garcia-Closas, M., Figueroa, J., Lissowska, J., Brinton, L., Czene, K., Darabi, H., Eriksson, M., Brand, J.S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Jager, A., Li, J.M., Liu, J.J., Humphreys, K., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Cross, S.S., Reed, M.W.R., Blot, W., Signorello, L.B., Cai, Q.Y., Pharoah, P.D.P., Perkins, B., Shah, M., Blows, F.M., Kang, D., Yoo, K.Y., Noh, D.Y., Hartman, M., Miao, H., Chia, K.S., Putti, T.C., Hamann, U., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C.S., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Sangrajrang, S., Gaborieau, V., Brennan, P., Mckay, J., Slager, S., Toland, A.E., Yannoukakos, D., Shen, C.Y., Hsiung, C.N., Wu, P.E., Ding, S.L., Ashworth, A., Jones, M., Orr, N., Swerdlow, A.J., Tsimiklis, H., Makalic, E., Schmidt, D.F., Bui, Q.M., Chanock, S.J., Hunter, D.J., Hein, R., Dahmen, N., Beckmann, L., Aaltonen, K., Muranen, T.A., Heikkinen, T., Irwanto, A., Rahman, N., Turnbull, C.A., Waisfisz, Q., Meijers-Heijboer, H.E.J., Adank, M.A., Luijt, R.B. van der, Hall, P., Chenevix-Trench, G., Dunning, A., Easton, D.F., Cox, A., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Breast Ovarian Canc Susceptibility, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Human Genetics, Human genetics, CCA - Oncogenesis, Ghoussaini, Maya [0000-0002-2415-2143], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Genotyping Techniques, Research Support, U.S. Gov't, P.H.S, CASP8 and FADD-Like Apoptosis Regulating Protein, Genome-wide association study, P.H.S, Medical and Health Sciences, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Medizinische Fakultät, Genetics(clinical), Non-U.S. Gov't, Genetics (clinical), Genetics, Genetics & Heredity, variants, Caspase 8, Research Support, Non-U.S. Gov't, Association Studies Articles, General Medicine, Biological Sciences, ddc, Chromosomes, Human, Pair 2, kConFab Investigators, Female, GENICA Network, Australian Ovarian Cancer Study Group, European Continental Ancestry Group, Non-P.H.S, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Research Support, Polymorphism, Single Nucleotide, White People, N.I.H, Breast cancer, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, medicine, Journal Article, Humans, Genetic Predisposition to Disease, ddc:610, gene, Genotyping, Molecular Biology, Genetic association, disease, Extramural, Proteins, Odds ratio, medicine.disease, susceptibility loci, Minor allele frequency, Case-Control Studies, genome-wide association, enhancers, U.S. Gov't, casp8, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regressionmodels adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10-5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P=3 × 10-6), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10-9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8might be the target gene, suggesting amechanism involving apoptosis.

Published
2016

20. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author

Hollestelle, Antoinette, van der Baan, Frederieke H., Berchuck, Andrew, Johnatty, Sharon E., Aben, Katja K., Agnarsson, Bjarni A., Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Antoniou, Antonis C., Apicella, Carmel, Arndt, Volker, Arnold, Norbert, Arun, Banu K., Arver, Brita, Ashworth, Alan, Baglietto, Laura, Balleine, Rosemary, Bandera, Elisa V., Barrowdale, Daniel, Bean, Yukie T., Beckmann, Lars, Beckmann, Matthias W., Benitez, Javier, Berger, Andreas, Berger, Raanan, Beuselinck, Benoit, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Bruning, Thomas, Butzow, Ralf, Leminen, Arto, Muranen, Taru A., Nevanlinna, Heli, Pelttari, Liisa M., Ovarian Canc Assoc Consortium, Breast Canc Assoc Consortium, Consortium Modifiers BRCA1 & BRCA2, Australian Ovarian Canc Study Grp, Breast Cancer Family Register, EMBRACE, GEMO Study Collaborators, GENICA Network, HEBON, kConFab Investigators, SWE-BRCA, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Pathology, Department of Obstetrics and Gynecology, and HUS Gynecology and Obstetrics

Subjects
RISK, SUSCEPTIBILITY LOCI, IDENTIFICATION, Clinical outcome, ENDOMETRIOSIS, 3122 Cancers, WOMEN, KRAS variant, Breast cancer, Ovarian cancer, 3123 Gynaecology and paediatrics, Genetic association, PROSTATE, GENOME-WIDE ASSOCIATION, POLYMORPHISMS, MICRORNA-BINDING-SITE
Abstract

Objective. Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods. Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results. We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 034, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions. rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers. (C) 2015 Elsevier Inc. All rights reserved.

Published
2016

21. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Author

Orr, Nick, Dudbridge, Frank, Dryden, Nicola, Maguire, Sarah, Novo, Daniela, Perrakis, Eleni, Johnson, Nichola, Ghoussaini, Maya, Hopper, John L., Southey, Melissa C., Apicella, Carmel, Stone, Jennifer, Schmidt, Marjanka K., Broeks, Annegien, Van't Veer, Laura J., Hogervorst, Frans B., Fasching, Peter A., Haeberle, Lothar, Ekici, Arif B., Beckmann, Matthias W., Gibson, Lorna, Aitken, Zoe, Warren, Helen, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Chistof, Guenel, Pascal, Truong, Therese, Cordina-Duverger, Emilie, Sanchez, Marie, Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Benitez, Javier, Zamora, Maria Pilar, Perez, Jose Ignacio Arias, Menendez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan L., Brenner, Hermann, Nevanlinna, Heli, Aittomaki, Kristiina, Blomqvist, Carl, Khan, Sofia, GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Department of Obstetrics and Gynecology, Clinicum, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, and Department of Oncology

Subjects
EXPRESSION, 3122 Cancers, 1184 Genetics, developmental biology, physiology, COMMON VARIANTS, ANALYSES REVEAL, 3123 Gynaecology and paediatrics, BINDING, CONFER SUSCEPTIBILITY, 1182 Biochemistry, cell and molecular biology, 3111 Biomedicine, GENOME-WIDE ASSOCIATION, ESTROGEN-RECEPTOR-ALPHA, FUNCTIONAL VARIANTS, FOXA1, RISK LOCUS
Abstract

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 x 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-alpha, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

Published
2015

22. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author

Michailidou, Kyriaki, Beesley, Jonathan, Lindstrom, Sara, Canisius, Sander, Dennis, Joe, Lush, Michael J., Maranian, Mel J., Bolla, Manjeet K., Wang, Qin, Shah, Mitul, Perkins, Barbara J., Czene, Kamila, Eriksson, Mikael, Darabi, Hatef, Brand, Judith S., Bojesen, Stig E., Nordestgaard, Borge G., Flyger, Henrik, Nielsen, Sune F., Rahman, Nazneen, Turnbull, Clare, Fletcher, Olivia, Peto, Julian, Gibson, Lorna, dos-Santos-Silva, Isabel, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Eilber, Ursula, Behrens, Sabine, Nevanlinna, Heli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Khan, Sofia, Aaltonen, Kirsimari, Ahsan, Habibul, Kibriya, Muhammad G., Whittemore, Alice S., John, Esther M., Malone, Kathleen E., Gammon, Marilie D., Santella, Regina M., Ursin, Giske, Makalic, Enes, Schmidt, Daniel F., Casey, Graham, Hunter, David J., van der Luijt, Rob B., Peeters, Petra, BOCS, KConFab Investigators, AOCS Grp, NBCS, and GENICA Network

Subjects
RISK, ESTROGEN, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Journal Article, CONFER SUSCEPTIBILITY, COMMON VARIANTS, ALLELES, GENOTYPE IMPUTATION, CHEK2-ASTERISK-1100DELC, BRCA1, OVARIAN-CANCER, METAANALYSIS
Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P

Published
2015

23. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Author

Orr, N., Dudbridge, F., Dryden, N., Maguire, S., Novo, D., Perrakis, E., Johnson, N., Ghoussaini, M., Hopper, J.L., Southey, M.C., Apicella, C., Stone, J., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Hogervorst, F.B., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Gibson, L., Aitken, Z., Warren, H., Sawyer, E., Tomlinson, I., Kerin, M.J., Miller, N., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Guenel, P., Truong, T., Cordina-Duverger, E., Sanchez, M., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Anton-Culver, H., Neuhausen, S.L., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Hamann, U., Brauch, H., Justenhoven, C., Bruning, T., Ko, Y.D., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Khan, S., Bogdanova, N., Dork, T., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Chenevix-Trench, G., Beesley, J., Lambrechts, D., Moisse, M., Floris, G., Beuselinck, B., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Radice, P., Peterlongo, P., Peissel, B., Pensotti, V., Couch, F.J., Olson, J.E., Slettedahl, S., Vachon, C., Giles, G.G., Milne, R.L., McLean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Kristensen, V., Alnaes, G.G., Nord, S., Borresen-Dale, A.L., Zheng, W., Deming-Halverson, S., Shrubsole, M., Long, J.R., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C.M., Asperen, C.J. van, Garcia-Closas, M., Figueroa, J., Chanock, S.J., Lissowska, J., Czene, K., Darabi, H., Eriksson, M., Klevebring, D., Hooning, M.J., Hollestelle, A., Deurzen, C.H.M. van, Kriege, M., Hall, P., Li, J.M., Liu, J.J., Humphreys, K., Cox, A., Cross, S.S., Reed, M.W.R., Pharoah, P.D.P., Dunning, A.M., Shah, M., Perkins, B.J., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Ashworth, A., Swerdlow, A., Jones, M., Schoemaker, M.J., Meindl, A., Schmutzler, R.K., Olswold, C., Slager, S., Toland, A.E., Yannoukakos, D., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Matsuo, K., Ito, H., Iwata, H., Ishiguro, J., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Teo, S.H., Yip, C.H., Kang, P., Ikram, M.K., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Kang, D., Choi, J.Y., Park, S.K., Noh, D.Y., Hartman, M., Miao, H., Lim, W.Y., Lee, S.C., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Wu, P.E., Hou, M.F., Yu, J.C., Shen, C.Y., Blot, W., Cai, Q.Y., Signorello, L.B., Luccarini, C., Bayes, C., Ahmed, S., Maranian, M., Healey, C.S., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrero, D., Tessier, D.C., Vincent, D., Bacot, F., Hunter, D.J., Lindstrom, S., Dennis, J., Michailidou, K., Bolla, M.K., Easton, D.F., Silva, I.D., Fletcher, O., Peto, J., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Obstetrics & Gynecology, Medical Oncology, Pathology, Ophthalmology, Cardiothoracic Surgery, and Clinical Genetics

Subjects
Asian Continental Ancestry Group, Adult, Hepatocyte Nuclear Factor 3-alpha, Risk, binding, European Continental Ancestry Group, Kruppel-Like Transcription Factors, estrogen-receptor-alpha, Breast Neoplasms, GATA3 Transcription Factor, Polymorphism, Single Nucleotide, White People, Kruppel-Like Factor 4, Asian People, SDG 3 - Good Health and Well-being, Medizinische Fakultät, common variants, expression, Humans, Genetic Predisposition to Disease, ddc:610, Genetic Association Studies, Aged, Association Studies Articles, Estrogen Receptor alpha, Chromosome Mapping, foxa1, Middle Aged, confer susceptibility, analyses reveal, Enhancer Elements, Genetic, risk locus, Genetic Loci, functional variants, genome-wide association, Female, Chromosomes, Human, Pair 9
Abstract

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. ispartof: Human Molecular Genetics vol:24 issue:10 pages:2966-84 ispartof: location:England status: published

Published
2015

24. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Author

Glubb, Dylan M., Maranian, Mel J., Michailidou, Kyriaki, Pooley, Karen A., Meyer, Kerstin B., Kar, Siddhartha, Carlebur, Saskia, O'Reilly, Martin, Betts, Joshua A., Hillman, Kristine M., Kaufmann, Susanne, Beesley, Jonathan, Canisius, Sander, Hopper, John L., Southey, Melissa C., Tsimiklis, Helen, Apicella, Carmel, Schmidt, Marjanka K., Broeks, Annegien, Hogervorst, Frans B., van der Schoot, C. Ellen, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A., Ruebner, Matthias, Ekici, Arif B., Beckmann, Matthias W., Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Pharoah, Paul D. P., Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Yang, Rongxi, Surowy, Harald, Guenel, Pascal, Nevanlinna, Heli, Muranen, Taru A., Aittomäki, Kristiina, Blomqvist, Carl, GENICA Network, kConFab Investigators, Norwegian Breast Canc Study, Department of Obstetrics and Gynecology, Department of Medical and Clinical Genetics, Department of Oncology, and HUS Gynecology and Obstetrics

Subjects
ACTIVATION, GENES, SUSCEPTIBILITY LOCI, PROMOTER, education, 3111 Biomedicine, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, CYCLIN D1 EXPRESSION, TUMORS, APOPTOSIS, SUBTYPES
Published
2015

25. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author

Hollestelle, A. (Antoinette), Baan, F.H. (Frederieke) van der, Berchuck, A. (Andrew), Johnatty, S.E. (Sharon), Aben, K.K.H. (Katja), Agnarsson, B.A. (Bjarni), Aittomäki, K. (Kristiina), Alducci, E. (Elisa), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia), Antoniou, A.C. (Antonis), Apicella, C. (Carmel), Arndt, V. (Volker), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Ashworth, A. (Alan), Baglietto, L. (Laura), Balleine, R. (Rosemary), Bandera, E.V. (Elisa), Barrowdale, D. (Daniel), Bean, Y.T. (Yukie), Beckmann, L. (Lars), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berger, A. (Andreas), Berger, R. (Raanan), Beuselinck, B. (B.), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet), Bonnani, B. (Bernardo), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Brüning, T. (Thomas), Budzilowska, A. (Agnieszka), Bunker, C.H. (Clareann H.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra S.), Caligo, M.A. (Maria), Campbell, I. (Ian), Carter, J. (Jonathan), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen J.), Claes, K.B.M. (Kathleen B.M.), Collée, J.M. (Margriet), Cook, L.S. (Linda S.), Couch, F.J. (Fergus), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cunningham, J.M. (Julie), Cybulski, C. (Cezary), Czene, K. (Kamila), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Hoya, M. (Miguel) de La, DeFazio, A. (Anna), Dennis, J. (Joe), Devilee, P. (Peter), Dicks, E. (Ed), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Du Bois, A. (Andreas), Dumont, M. (Martine), Dunning, A.M. (Alison), Duran, M. (Mercedes), Easton, D.F. (Douglas F.), Eccles, D. (Diana), Edwards, R. (Robert), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S.D. (Steve), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Fontaine, A. (Annette), Fortuzzi, S. (S.), Fostira, F. (Florentia), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Friel, G. (Grace), Frost, D. (Debra), Garber, J. (Judy), García-Closas, M. (Montserrat), Gayther, S.A. (Simon), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Goodman, M.T. (Marc T.), Gore, M. (Martin), Greene, M.H. (Mark H.), Grip, M. (Mervi), Gronwald, J. (Jacek), Gschwantler-Kaulich, D. (Daphne), Guénel, P. (Pascal), Guzman, S.R. (Starr R.), Haeberle, L. (Lothar), Haiman, C.A. (Christopher A.), Hall, P. (Per), Halverson, S.L. (Sandra L.), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Harter, P. (Philipp), Hartikainen, J.M. (J.), Healey, S. (Sue), Hein, R. (Rebecca), Heitz, P.U., Henderson, B.E. (Brian), Herzog, J. (Josef), Hildebrandt, M.A.T. (Michelle), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans), Hopper, J.L. (John), Humphreys, K. (Keith), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny N.), Isaacs, C. (Claudine), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jaworska, K. (Katarzyna), Jensen, A. (Allan), Jensen, U.B., Johnson, N. (Nichola), Jukkola-Vuorinen, A. (Arja), Kabisch, M. (Maria), Karlan, B.Y. (Beth Y.), Kataja, V. (Vesa), Kauff, N. (Noah), Kelemen, L.E. (Linda), Kerin, M. (Michael), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Knol-Bout, J.P. (Jacoba P.), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Krakstad, C. (Camilla), Kristensen, V. (Vessela), Kuchenbaecker, K.B. (Karoline), Kupryjanczyk, J. (Jolanta), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lambrechts, S. (Sandrina), Larson, M.C. (Melissa), Lasa, A. (Adriana), Laurent-Puig, P. (Pierre), Lázaro, C. (Conxi), Le, N. (Nhu), Le Marchand, L. (Loic), Leminen, A. (Arto), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Liang, D. (Dong), Lindblom, A. (Annika), Lindor, N.M. (Noralane), Lissowska, J. (Jolanta), Long, J. (Jirong), Lu, K.H. (Karen), Lubinski, J. (Jan), Lundvall, L. (Lene), Lurie, G. (Galina), Mai, P.L. (Phuong), Mannermaa, A. (Arto), Margolin, S. (Sara), Mariette, F. (F.), Marme, F. (Federick), Martens, J.W.M. (John), Massuger, L.F. (Leon), Maugard, C., Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McGuire, W.P., McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menegaux, F. (Florence), Menéndez, P. (Primitiva), Menkiszak, J. (Janusz), Menon, U. (Usha), Mensenkamp, A.R. (Arjen), Miller, N. (Nicola), Milne, R.L. (Roger), Modugno, F. (Francesmary), Montagna, M. (Marco), Moysich, K.B. (Kirsten B.), Müller, H. (Heiko), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru), Narod, S.A. (Steven A.), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta B.), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, F. (Finn), Nielsen, S.F. (Sune), Nordestgaard, B.G. (Børge), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olson, S.H. (Sara), Oosterwijk, J.C. (Jan), Orlow, I. (Irene), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Ottini, L. (Laura), Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Sokilde), Peissel, B. (Bernard), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa), Perkins, J. (Jo), Permuth-Wey, J. (Jenny), Peterlongo, P. (Paolo), Peto, J. (Julian), Phelan, C. (Catherine), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm C.), Platte, R. (Radka), Plisiecka-Halasa, J. (Joanna), Poole, E.M. (Elizabeth), Poppe, B. (Bruce), Pykäs, K. (Katri), Radice, P. (Paolo), Ramus, S.J. (Susan), Rebbeck, R. (Timothy), Reed, M.W.R. (Malcolm W.R.), Rennert, G. (Gad), Risch, H. (Harvey), Robson, M. (Mark), Rodriguez, G. (Gustavo), Romero, A. (Atocha), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salani, R. (Ritu), Salvesen, H.B. (Helga), Sawyer, E.J. (Elinor), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Schneeweiss, A. (Andreas), Schoemaker, M. (Minouk), Schrauder, A. (André), Schumacher, F.R. (Fredrick), Schwaab, I. (Ira), Scuvera, G. (Giulietta), Sellers, T.A. (Thomas A.), Severi, G. (Gianluca), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shrubsole, M. (Martha), Siddiqui, N. (Nadeem), Sieh, W. (Weiva), Simard, J. (Jacques), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Smeets, D. (Dominiek), Sohn, C. (Christof), Soller, M. (Maria), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stegmaier, C. (Christa), Stoppa-Lyonnet, D. (Dominique), Sucheston, L. (Lara), Swerdlow, A.J. (Anthony ), Tangen, I.L. (Ingvild L.), Tea, M.-K., Teixeira, P.J., Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Thompson, P.J. (Pamela J.), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tsimiklis, H. (Helen), Tung, N. (Nadine), Tworoger, S. (Shelley), Tyrer, J.P. (Jonathan), Vachon, C. (Celine), Veer, L.J. (Laura) van 't, Altena, A.M. (Anne) van, Asperen, C.J. (Christi) van, Van Den Berg, D. (David), Ouweland, A.M.W. (Ans) van den, Doorn, H.C. (Lena) van, Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vergote, I. (Ignace), Verhoef, S., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vitonis, A.F. (Allison), Wachenfeldt, A. (Anna) von, Walsh, C.S. (Christine), Wang, Q. (Qing), Wang-Gohrke, S. (Shan), Wapenschmidt, B. (Barbara), Weischer, M. (Maren), Weitzel, J.N. (Jeffrey), Weltens, C. (Caroline), Wentzensen, N. (N.), Whittemore, A.S. (Alice S.), Wilkens, L.R. (Lynne R.), Winqvist, R. (Robert), Wu, A.H. (Anna), Wu, X. (Xifeng), Yang, H.P. (Hannah P.), Zaffaroni, D. (Daniela), Zamora, M.P. (Pilar), Zheng, W. (Wei), Ziogas, A. (Argyrios), Chenevix-Trench, G. (Georgia), Pharoah, P.D.P. (Paul), Rookus, M.A. (Matti), Hooning, M.J. (Maartje), Goode, E.L. (Ellen L.), Breast Cancer Family Register, EMBRACE, GENICA Network, HEBON, SWE-BRCA, Hollestelle, A. (Antoinette), Baan, F.H. (Frederieke) van der, Berchuck, A. (Andrew), Johnatty, S.E. (Sharon), Aben, K.K.H. (Katja), Agnarsson, B.A. (Bjarni), Aittomäki, K. (Kristiina), Alducci, E. (Elisa), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N.N. (Natalia), Antoniou, A.C. (Antonis), Apicella, C. (Carmel), Arndt, V. (Volker), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita Wasteson), Ashworth, A. (Alan), Baglietto, L. (Laura), Balleine, R. (Rosemary), Bandera, E.V. (Elisa), Barrowdale, D. (Daniel), Bean, Y.T. (Yukie), Beckmann, L. (Lars), Beckmann, M.W. (Matthias), Benítez, J. (Javier), Berger, A. (Andreas), Berger, R. (Raanan), Beuselinck, B. (B.), Bisogna, M. (Maria), Bjorge, L. (Line), Blomqvist, C. (Carl), Bogdanova, N.V. (Natalia), Bojesen, A. (Anders), Bojesen, S.E. (Stig), Bolla, M.K. (Manjeet), Bonnani, B. (Bernardo), Brand, J.S. (Judith S.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brinton, L.A. (Louise), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Brüning, T. (Thomas), Budzilowska, A. (Agnieszka), Bunker, C.H. (Clareann H.), Burwinkel, B. (Barbara), Butzow, R. (Ralf), Buys, S.S. (Saundra S.), Caligo, M.A. (Maria), Campbell, I. (Ian), Carter, J. (Jonathan), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen J.), Claes, K.B.M. (Kathleen B.M.), Collée, J.M. (Margriet), Cook, L.S. (Linda S.), Couch, F.J. (Fergus), Cox, A. (Angela), Cramer, D.W. (Daniel), Cross, S.S. (Simon), Cunningham, J.M. (Julie), Cybulski, C. (Cezary), Czene, K. (Kamila), Damiola, F. (Francesca), Dansonka-Mieszkowska, A. (Agnieszka), Darabi, H. (Hatef), Hoya, M. (Miguel) de La, DeFazio, A. (Anna), Dennis, J. (Joe), Devilee, P. (Peter), Dicks, E. (Ed), Díez, O. (Orland), Doherty, J.A. (Jennifer A.), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Santos Silva, I. (Isabel) dos, Du Bois, A. (Andreas), Dumont, M. (Martine), Dunning, A.M. (Alison), Duran, M. (Mercedes), Easton, D.F. (Douglas F.), Eccles, D. (Diana), Edwards, R. (Robert), Ehrencrona, H. (Hans), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S.D. (Steve), Engel, C. (Christoph), Eriksson, M. (Mikael), Fasching, P.A. (Peter), Feliubadaló, L. (L.), Figueroa, J.D. (Jonine), Flesch-Janys, D. (Dieter), Fletcher, O. (Olivia), Fontaine, A. (Annette), Fortuzzi, S. (S.), Fostira, F. (Florentia), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Friel, G. (Grace), Frost, D. (Debra), Garber, J. (Judy), García-Closas, M. (Montserrat), Gayther, S.A. (Simon), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Goodman, M.T. (Marc T.), Gore, M. (Martin), Greene, M.H. (Mark H.), Grip, M. (Mervi), Gronwald, J. (Jacek), Gschwantler-Kaulich, D. (Daphne), Guénel, P. (Pascal), Guzman, S.R. (Starr R.), Haeberle, L. (Lothar), Haiman, C.A. (Christopher A.), Hall, P. (Per), Halverson, S.L. (Sandra L.), Hamann, U. (Ute), Hansen, T.V.O. (Thomas), Harter, P. (Philipp), Hartikainen, J.M. (J.), Healey, S. (Sue), Hein, R. (Rebecca), Heitz, P.U., Henderson, B.E. (Brian), Herzog, J. (Josef), Hildebrandt, M.A.T. (Michelle), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans), Hopper, J.L. (John), Humphreys, K. (Keith), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny N.), Isaacs, C. (Claudine), Jakubowska, A. (Anna), Janavicius, R. (Ramunas), Jaworska, K. (Katarzyna), Jensen, A. (Allan), Jensen, U.B., Johnson, N. (Nichola), Jukkola-Vuorinen, A. (Arja), Kabisch, M. (Maria), Karlan, B.Y. (Beth Y.), Kataja, V. (Vesa), Kauff, N. (Noah), Kelemen, L.E. (Linda), Kerin, M. (Michael), Kiemeney, L.A.L.M. (Bart), Kjaer, M. (Michael), Knight, J.A. (Julia), Knol-Bout, J.P. (Jacoba P.), Konstantopoulou, I. (I.), Kosma, V-M. (Veli-Matti), Krakstad, C. (Camilla), Kristensen, V. (Vessela), Kuchenbaecker, K.B. (Karoline), Kupryjanczyk, J. (Jolanta), Laitman, Y. (Yael), Lambrechts, D. (Diether), Lambrechts, S. (Sandrina), Larson, M.C. (Melissa), Lasa, A. (Adriana), Laurent-Puig, P. (Pierre), Lázaro, C. (Conxi), Le, N. (Nhu), Le Marchand, L. (Loic), Leminen, A. (Arto), Lester, K.J. (Kathryn), Levine, D.A. (Douglas), Li, J. (Jingmei), Liang, D. (Dong), Lindblom, A. (Annika), Lindor, N.M. (Noralane), Lissowska, J. (Jolanta), Long, J. (Jirong), Lu, K.H. (Karen), Lubinski, J. (Jan), Lundvall, L. (Lene), Lurie, G. (Galina), Mai, P.L. (Phuong), Mannermaa, A. (Arto), Margolin, S. (Sara), Mariette, F. (F.), Marme, F. (Federick), Martens, J.W.M. (John), Massuger, L.F. (Leon), Maugard, C., Mazoyer, S. (Sylvie), McGuffog, L. (Lesley), McGuire, W.P., McLean, C.A. (Catriona Ann), McNeish, I. (Iain), Meindl, A. (Alfons), Menegaux, F. (Florence), Menéndez, P. (Primitiva), Menkiszak, J. (Janusz), Menon, U. (Usha), Mensenkamp, A.R. (Arjen), Miller, N. (Nicola), Milne, R.L. (Roger), Modugno, F. (Francesmary), Montagna, M. (Marco), Moysich, K.B. (Kirsten B.), Müller, H. (Heiko), Mulligan, A.-M. (Anna-Marie), Muranen, T.A. (Taru), Narod, S.A. (Steven A.), Nathanson, K.L. (Katherine), Ness, R.B. (Roberta B.), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Neven, P. (Patrick), Nielsen, F. (Finn), Nielsen, S.F. (Sune), Nordestgaard, B.G. (Børge), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Offit, K. (Kenneth), Olah, E., Olopade, O.I. (Olufunmilayo I.), Olson, J.E. (Janet), Olson, S.H. (Sara), Oosterwijk, J.C. (Jan), Orlow, I. (Irene), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Ottini, L. (Laura), Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Sokilde), Peissel, B. (Bernard), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa), Perkins, J. (Jo), Permuth-Wey, J. (Jenny), Peterlongo, P. (Paolo), Peto, J. (Julian), Phelan, C. (Catherine), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm C.), Platte, R. (Radka), Plisiecka-Halasa, J. (Joanna), Poole, E.M. (Elizabeth), Poppe, B. (Bruce), Pykäs, K. (Katri), Radice, P. (Paolo), Ramus, S.J. (Susan), Rebbeck, R. (Timothy), Reed, M.W.R. (Malcolm W.R.), Rennert, G. (Gad), Risch, H. (Harvey), Robson, M. (Mark), Rodriguez, G. (Gustavo), Romero, A. (Atocha), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salani, R. (Ritu), Salvesen, H.B. (Helga), Sawyer, E.J. (Elinor), Schildkraut, J.M. (Joellen), Schmidt, M.K. (Marjanka), Schmutzler, R.K. (Rita), Schneeweiss, A. (Andreas), Schoemaker, M. (Minouk), Schrauder, A. (André), Schumacher, F.R. (Fredrick), Schwaab, I. (Ira), Scuvera, G. (Giulietta), Sellers, T.A. (Thomas A.), Severi, G. (Gianluca), Seynaeve, C.M. (Caroline), Shah, M. (Mitul), Shrubsole, M. (Martha), Siddiqui, N. (Nadeem), Sieh, W. (Weiva), Simard, J. (Jacques), Singer, C.F. (Christian), Sinilnikova, O. (Olga), Smeets, D. (Dominiek), Sohn, C. (Christof), Soller, M. (Maria), Song, H. (Honglin), Soucy, P. (Penny), Southey, M.C. (Melissa), Stegmaier, C. (Christa), Stoppa-Lyonnet, D. (Dominique), Sucheston, L. (Lara), Swerdlow, A.J. (Anthony ), Tangen, I.L. (Ingvild L.), Tea, M.-K., Teixeira, P.J., Terry, K.L. (Kathryn), Terry, M.B. (Mary Beth), Thomassen, M. (Mads), Thompson, P.J. (Pamela J.), Tihomirova, L. (Laima), Tischkowitz, M. (Marc), Toland, A.E. (Amanda), Tollenaar, R.A.E.M. (Rob), Tomlinson, I. (Ian), Torres, D. (Diana), Truong, T. (Thérèse), Tsimiklis, H. (Helen), Tung, N. (Nadine), Tworoger, S. (Shelley), Tyrer, J.P. (Jonathan), Vachon, C. (Celine), Veer, L.J. (Laura) van 't, Altena, A.M. (Anne) van, Asperen, C.J. (Christi) van, Van Den Berg, D. (David), Ouweland, A.M.W. (Ans) van den, Doorn, H.C. (Lena) van, Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vergote, I. (Ignace), Verhoef, S., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vitonis, A.F. (Allison), Wachenfeldt, A. (Anna) von, Walsh, C.S. (Christine), Wang, Q. (Qing), Wang-Gohrke, S. (Shan), Wapenschmidt, B. (Barbara), Weischer, M. (Maren), Weitzel, J.N. (Jeffrey), Weltens, C. (Caroline), Wentzensen, N. (N.), Whittemore, A.S. (Alice S.), Wilkens, L.R. (Lynne R.), Winqvist, R. (Robert), Wu, A.H. (Anna), Wu, X. (Xifeng), Yang, H.P. (Hannah P.), Zaffaroni, D. (Daniela), Zamora, M.P. (Pilar), Zheng, W. (Wei), Ziogas, A. (Argyrios), Chenevix-Trench, G. (Georgia), Pharoah, P.D.P. (Paul), Rookus, M.A. (Matti), Hooning, M.J. (Maartje), Goode, E.L. (Ellen L.), Breast Cancer Family Register, EMBRACE, GENICA Network, HEBON, and SWE-BRCA

Abstract

Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and br

Published
2016
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26. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Author

Milne, R.L., Burwinkel, B., Michailidou, K., Arias-Perez, J.I., Zamora, M.P., Menendez-Rodriguez, P., Hardisson, D., Mendiola, M., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Dennis, J., Wang, Q., Bolla, M.K., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M., Ko, Y.D., Brauch, H., Hamann, U., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Li, J.M., Brand, J.S., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Lambrechts, D., Peuteman, G., Christiaens, M.R., Smeets, A., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Hartman, M., Hui, M., Lim, W.Y., Chan, C.W., Marme, F., Yang, R.X., Bugert, P., Lindblom, A., Margolin, S., Garcia-Closas, M., Chanock, S.J., Lissowska, J., Figueroa, J.D., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Hooning, M.J., Kriege, M., Ouweland, A.M.W. van den, Koppert, L.B., Fletcher, O., Johnson, N., Dos-Santos-Silva, I., Peto, J., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Cox, A., Cross, S.S., Reed, M.W.R., Schmidt, M.K., Broeks, A., Cornelissen, S., Braaf, L., Kang, D., Choi, J.Y., Park, S.K., Noh, D.Y., Simard, J., Dumont, M., Goldberg, M.S., Labreche, F., Fasching, P.A., Hein, A., Ekici, A.B., Beckmann, M.W., Radice, P., Peterlongo, P., Azzollini, J., Barile, M., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Hopper, J.L., Schmidt, D.F., Makalic, E., Southey, M.C., Teo, S.H., Yip, C.H., Sivanandan, K., Tay, W.T., Shen, C.Y., Hsiung, C.N., Yu, J.C., Hou, M.F., Guenel, P., Truong, T., Sanchez, M., Mulot, C., Blot, W., Cai, Q.Y., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Bogdanova, N., Dork, T., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Shu, X.O., Lu, W., Gao, Y.T., Zhang, B., Couch, F.J., Toland, A.E., Yannoukakos, D., Sangrajrang, S., McKay, J., Wang, X.S., Olson, J.E., Vachon, C., Purrington, K., Severi, G., Baglietto, L., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Czene, K., Eriksson, M., Humphreys, K., Darabi, H., Ahmed, S., Shah, M., Pharoah, P.D.P., Hall, P., Giles, G.G., Benitez, J., Dunning, A.M., Chenevix-Trench, G., Easton, D.F., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, TNBCC, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Adult, Ataxin-7, A Kinase Anchor Proteins, Breast Neoplasms, Nerve Tissue Proteins, Middle Aged, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Cytoskeletal Proteins, Case-Control Studies, Humans, NIMA-Related Kinases, Female, Genetic Predisposition to Disease, health care economics and organizations, Alleles, Genome-Wide Association Study
Abstract

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility\ud variants, although most studies have been underpowered to detect associations of a realistic magnitude.\ud We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which\ud evidence of association with breast cancer risk had been previously reported. Case-control data were combined\ud from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional\ud logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21\ud [rs1053338, per allele OR 5 1.07, 95% confidence interval (CI) 5 1.04–1.10, P 5 2.9 3 1026\ud ], AKAP9-M463I at\ud 7q21 (rs6964587, OR 5 1.05, 95% CI 5 1.03–1.07, P 5 1.7 3 1026\ud ) and NEK10-L513S at 3p24 (rs10510592,\ud OR 5 1.10, 95% CI 5 1.07 –1.12, P 5 5.1 3 10217). The first two associations reached genome-wide statistical\ud significance in a combined analysis of available data, including independent data from nine genome-wide association\ud studies (GWASs): for ATXN7-K264R, OR 5 1.07 (95% CI 5 1.05–1.10, P 5 1.0 3 1028\ud ); for AKAP9-M463I,\ud OR 5 1.05 (95% CI 5 1.04–1.07, P 5 2.0 3 10210). Further analysis of other common variants in these two\ud regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified\ud a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is\ud associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility\ud region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of\ud the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast\ud cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying\ud variants and the genes through which they act.

Published
2014

27. Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

Author

Sawyer, Elinor, Roylance, Rebecca, Petridis, Christos, Brook, Mark N., Nowinski, Salpie, Papouli, Efterpi, Fletcher, Olivia, Pinder, Sarah, Hanby, Andrew, Kohut, Kelly, Gorman, Patricia, Caneppele, Michele, Peto, Julian, Silva, Isabel dos Santos, Johnson, Nichola, Swann, Ruth, Dwek, Miriam, Perkins, Katherine-Anne, Gillett, Cheryl, Houlston, Richard, Ross, Gillian, De Ieso, Paolo, Southey, Melissa C., Hopper, John L., Provenzano, Elena, Apicella, Carmel, Wesseling, Jelle, Cornelissen, Sten, Keeman, Renske, Fasching, Peter A., Jud, Sebastian M., Ekici, Arif B., Beckmann, Matthias W., Kerin, Michael J., Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guenel, Pascal, Truong, Therese, Laurent-Puig, Pierre, Kerbrat, Pierre, Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Nevanlinna, Heli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, GENICA Network, kConFab Investigators, Department of Obstetrics and Gynecology, Clinicum, Haartman Institute (-2014), Department of Medical and Clinical Genetics, Department of Oncology, and HUS Gynecology and Obstetrics

Subjects
RISK, education, 3122 Cancers, IDENTIFIES 3, COMMON VARIANTS, MUTATION CARRIERS, 14Q24.1 RAD51L1, CHEMOTHERAPY, CANCER SUSCEPTIBILITY LOCI, 3123 Gynaecology and paediatrics, CONFER SUSCEPTIBILITY, 3111 Biomedicine, GENOME-WIDE ASSOCIATION, METAANALYSIS
Published
2014

28. MicroRNA related polymorphisms and breast cancer risk

Author

Khan, S., Greco, D., Michailidou, K., Milne, R.L., Muranen, T.A., Heikkinen, T., Aaltonen, K., Dennis, J., Bolla, M.K., Liu, J., Hall, P., Irwanto, A., Humphreys, K., Li, J., Czene, K., Chang-Claude, J., Hein, R., Rudolph, A., Seibold, P., Flesch-Janys, D., Fletcher, O., Peto, J., Silva, I.D., Johnson, N., Gibson, L., Aitken, Z., Hopper, J.L., Tsimiklis, H., Bui, M., Makalic, E., Schmidt, D.F., Southey, M.C., Apicella, C., Stone, J., Waisfisz, Q., Meijers-Heijboer, H., Adank, M.A., Luijt, R.B. van der, Meindl, A., Schmutzler, R.K., Muller-Myhsok, B., Lichtner, P., Turnbull, C., Rahman, N., Chanock, S.J., Hunter, D.J., Cox, A., Cross, S.S., Reed, M.W.R., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Hogervorst, F.B., Fasching, P.A., Schrauder, M.G., Ekici, A.B., Beckmann, M.W., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, P.M., Perez, J.I.A., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Pharoah, P.D.P., Dunning, A.M., Shah, M., Luben, R., Brown, J., Couch, F.J., Wang, X., Vachon, C., Olson, J.E., Lambrechts, D., Moisse, M., Paridaens, R., Christiaens, M.R., Guenel, P., Truong, T., Laurent-Puig, P., Mulot, C., Marme, F., Burwinkel, B., Schneeweiss, A., Sohn, C., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Andrulis, I.L., Knight, J.A., Tchatchou, S., Mulligan, A.M., Dork, T., Bogdanova, N.V., Antonenkova, N.N., Anton-Culver, H., Darabi, H., Eriksson, M., Garcia-Closas, M., Figueroa, J., Lissowska, J., Brinton, L., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Kristensen, V.N., Slager, S., Toland, A.E., Ambrosone, C.B., Yannoukakos, D., Lindblom, A., Margolin, S., Radice, P., Peterlongo, P., Barile, M., Mariani, P., Hooning, M.J., Martens, J.W.M., Collee, J.M., Jager, A., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Giles, G.G., McLean, C., Brauch, H., Bruning, T., Ko, Y.D., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Swerdlow, A., Ashworth, A., Orr, N., Jones, M., Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Kataja, V., Kosma, V.M., Hartikainen, J.M., Mannermaa, A., Hamann, U., Chenevix-Trench, G., Blomqvist, C., Aittomaki, K., Easton, D.F., Nevanlinna, H., KConFab Investigators, Australian Ovarian Canc Study Grp, GENICA Network, Department of Obstetrics and Gynecology, Clinicum, Department of Oncology, Haartman Institute (-2014), Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Human genetics, CCA - Oncogenesis, Obstetrics & Gynecology, Medical Oncology, Erasmus MC other, and Clinical Genetics

Subjects
Heredity, IDENTIFIES 3, lcsh:Medicine, Estrogen receptor, Genome-wide association study, Bioinformatics, 3123 Gynaecology and paediatrics, HUMAN GENES, lcsh:Science, 3' Untranslated Regions, Multidisciplinary, Research Support, Non-U.S. Gov't, Chromosome Mapping, SINGLE-NUCLEOTIDE POLYMORPHISMS, 3. Good health, Receptors, Estrogen, Female, CASP8 GENE, Research Article, EXPRESSION, Genotype, SUSCEPTIBILITY LOCI, education, 3122 Cancers, MiRNA binding, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Genetic Predisposition, Polymorphism, Single Nucleotide, BINDING-SITES, Breast cancer, REDUCED RISK, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, microRNA, Genetic predisposition, medicine, Journal Article, Genetics, Cancer Genetics, Humans, GENOME-WIDE ASSOCIATION, Drosha, Genetic Association Studies, Binding Sites, Complex Traits, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, medicine.disease, Research Support, N.I.H., Intramural, COMMON VARIANT, MicroRNAs, Case-Control Studies, Genetics of Disease, lcsh:Q, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95 confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95 CI: 0.95-0.99), rs10719 (OR 0.97; 95 Cl: 0.94-0.99), rs4687554 (OR 0.97; 95 CI: 0.95-0.99, and rs3134615 (OR 1.03; 95 CI: 1.01 -1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects. This is an open-access article free of all copyright.

Published
2014

29. Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.

Author

Glubb, Dylan M, Glubb, Dylan M, Maranian, Mel J, Michailidou, Kyriaki, Pooley, Karen A, Meyer, Kerstin B, Kar, Siddhartha, Carlebur, Saskia, O'Reilly, Martin, Betts, Joshua A, Hillman, Kristine M, Kaufmann, Susanne, Beesley, Jonathan, Canisius, Sander, Hopper, John L, Southey, Melissa C, Tsimiklis, Helen, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, van der Schoot, C Ellen, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Ruebner, Matthias, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Pharoah, Paul DP, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Yang, Rongxi, Surowy, Harald, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, González-Neira, Anna, Benitez, Javier, Zamora, M Pilar, Arias Perez, Jose Ignacio, Anton-Culver, Hoda, Neuhausen, Susan L, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Ko, Yon-Dschun, Brüning, Thomas, GENICA Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tanaka, Hideo, Dörk, Thilo, Bogdanova, Natalia V, Helbig, Sonja, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, kConFab Investigators, Wu, Anna H, Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O, Lambrechts, Diether, Zhao, Hui, Weltens, Caroline, van Limbergen, Erik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Radice, Paolo, Glubb, Dylan M, Glubb, Dylan M, Maranian, Mel J, Michailidou, Kyriaki, Pooley, Karen A, Meyer, Kerstin B, Kar, Siddhartha, Carlebur, Saskia, O'Reilly, Martin, Betts, Joshua A, Hillman, Kristine M, Kaufmann, Susanne, Beesley, Jonathan, Canisius, Sander, Hopper, John L, Southey, Melissa C, Tsimiklis, Helen, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, van der Schoot, C Ellen, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Ruebner, Matthias, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Pharoah, Paul DP, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Yang, Rongxi, Surowy, Harald, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, González-Neira, Anna, Benitez, Javier, Zamora, M Pilar, Arias Perez, Jose Ignacio, Anton-Culver, Hoda, Neuhausen, Susan L, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Ko, Yon-Dschun, Brüning, Thomas, GENICA Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tanaka, Hideo, Dörk, Thilo, Bogdanova, Natalia V, Helbig, Sonja, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, kConFab Investigators, Wu, Anna H, Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O, Lambrechts, Diether, Zhao, Hui, Weltens, Caroline, van Limbergen, Erik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, and Radice, Paolo

Abstract

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

Published
2015

30. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author

Epi Kanker Team 1, JC onderzoeksprogramma Kanker, Cancer, Genetica Sectie Genoomdiagnostiek, Michailidou, Kyriaki, Beesley, Jonathan, Lindstrom, Sara, Canisius, Sander, Dennis, Joe, Lush, Michael J., Maranian, Mel J., Bolla, Manjeet K., Wang, Qin, Shah, Mitul, Perkins, Barbara J., Czene, Kamila, Eriksson, Mikael, Darabi, Hatef, Brand, Judith S., Bojesen, Stig E., Nordestgaard, Borge G., Flyger, Henrik, Nielsen, Sune F., Rahman, Nazneen, Turnbull, Clare, Fletcher, Olivia, Peto, Julian, Gibson, Lorna, dos-Santos-Silva, Isabel, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Eilber, Ursula, Behrens, Sabine, Nevanlinna, Heli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Khan, Sofia, Aaltonen, Kirsimari, Ahsan, Habibul, Kibriya, Muhammad G., Whittemore, Alice S., John, Esther M., Malone, Kathleen E., Gammon, Marilie D., Santella, Regina M., Ursin, Giske, Makalic, Enes, Schmidt, Daniel F., Casey, Graham, Hunter, David J., van der Luijt, Rob B., Peeters, Petra, BOCS, KConFab Investigators, AOCS Grp, NBCS, GENICA Network, Epi Kanker Team 1, JC onderzoeksprogramma Kanker, Cancer, Genetica Sectie Genoomdiagnostiek, Michailidou, Kyriaki, Beesley, Jonathan, Lindstrom, Sara, Canisius, Sander, Dennis, Joe, Lush, Michael J., Maranian, Mel J., Bolla, Manjeet K., Wang, Qin, Shah, Mitul, Perkins, Barbara J., Czene, Kamila, Eriksson, Mikael, Darabi, Hatef, Brand, Judith S., Bojesen, Stig E., Nordestgaard, Borge G., Flyger, Henrik, Nielsen, Sune F., Rahman, Nazneen, Turnbull, Clare, Fletcher, Olivia, Peto, Julian, Gibson, Lorna, dos-Santos-Silva, Isabel, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Eilber, Ursula, Behrens, Sabine, Nevanlinna, Heli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Khan, Sofia, Aaltonen, Kirsimari, Ahsan, Habibul, Kibriya, Muhammad G., Whittemore, Alice S., John, Esther M., Malone, Kathleen E., Gammon, Marilie D., Santella, Regina M., Ursin, Giske, Makalic, Enes, Schmidt, Daniel F., Casey, Graham, Hunter, David J., van der Luijt, Rob B., Peeters, Petra, BOCS, KConFab Investigators, AOCS Grp, NBCS, and GENICA Network

Published
2015

31. Breast cancer risk and 6q22.33: Combined results from breast cancer association consortium and consortium of investigators on modifiers of brca1/2

Author

Kirchhoff, T., Gaudet, M.M., Antoniou, A.C., McGuffog, L., Humphreys, M.K., Dunning, A.M., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Kang, D., Yoo, K.Y., Noh, D.Y., Ahn, S.H., Dork, T., Schurmann, P., Karstens, J.H., Hillemanns, P., Couch, F.J., Olson, J., Vachon, C., Wang, X.S., Cox, A., Brock, I., Elliott, G., Reed, M.W.R., Burwinkel, B., Meindl, A., Brauch, H., Hamann, U., Ko, Y.D., Broeks, A., Schmidt, M.K., Veer, L.J. van 't, Braaf, L.M., Johnson, N., Fletcher, O., Gibson, L., Peto, J., Turnbull, C., Seal, S., Renwick, A., Rahman, N., Wu, P.E., Yu, J.C., Hsiung, C.N., Shen, C.Y., Southey, M.C., Hopper, J.L., Hammet, F., Dorpe, T. van, Dieudonne, A.S., Hatse, S., Lambrechts, D., Andrulis, I.L., Bogdanova, N., Antonenkova, N., Rogov, J.I., Prokofieva, D., Bermisheva, M., Khusnutdinova, E., Asperen, C.J. van, Tollenaar, R.A.E.M., Hooning, M.J., Devilee, P., Margolin, S., Lindblom, A., Milne, R.L., Arias, J.I., Zamora, M.P., Benitez, J., Severi, G., Baglietto, L., Giles, G.G., Spurdle, A.B., Beesley, J., Chen, X.Q., Holland, H., Healey, S., Wang-Gohrke, S., Chang-Claude, J., Mannermaa, A., Kosma, V.M., Kauppinen, J., Kataja, V., Agnarsson, B.A., Caligo, M.A., Godwin, A.K., Nevanlinna, H., Heikkinen, T., Fredericksen, Z., Lindor, N., Nathanson, K.L., Domchek, S.M., Loman, N., Karlsson, P., Askmalm, M.S., Melin, B., Wachenfeldt, A. von, Hogervorst, F.B.L., Verheus, M., Rookus, M.A., Seynaeve, C., Oldenburg, R.A., Ligtenberg, M.J., Ausems, M.G.E.M., Aalfs, C.M., Gille, H.J.P., Wijnen, J.T., Garcia, E.B.G., Peock, S., Cook, M., Oliver, C.T., Frost, D., Luccarini, C., Pichert, G., Davidson, R., Chu, C., Eccles, D., Ong, K.R., Cook, J., Douglas, F., Hodgson, S., Evans, D.G., Eeles, R., Gold, B., Pharoah, P.D.P., Offit, K., Chenevix-Trench, G., Easton, D.F., GENICA Network, kConFab, AOCS Study Grp, SWE-BRCA, HEBON, EMBRACE, BCAC-CIMBA, Medical Oncology, Clinical Genetics, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Department of Obstetrics and Gynecology, Women's Health Research Program, Human Genetics, Cancer Center Amsterdam, and Amsterdam Reproduction & Development (AR&D)

Subjects
Oncology, Genetics and Molecular Biology (all), Medicin och hälsovetenskap, Alleles, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Chromosomes, Human, Pair 6, Confidence Intervals, Female, Genetic Association Studies, Heterozygote, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Proportional Hazards Models, Receptors, Estrogen, Risk Factors, Genetic Predisposition to Disease, Medicine (all), Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Epidemiology, Genome-wide association study, VARIANTS, Bioinformatics, Medical and Health Sciences, Biochemistry, 0302 clinical medicine, Breast Tumors, Genotype, Receptors, skin and connective tissue diseases, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), 0303 health sciences, education.field_of_study, variants, Multidisciplinary, Cancer Risk Factors, Obstetrics and Gynecology, Single Nucleotide, 3. Good health, Genetic Epidemiology, 030220 oncology & carcinogenesis, alleles, Medicine, Pair 6, Cancer Epidemiology, Research Article, Human, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Science, Genetic Causes of Cancer, Population, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], education, Single-nucleotide polymorphism, Chromosomes, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Internal medicine, Breast Cancer, Genetics, Cancer Genetics, Genome-Wide Association Studies, medicine, GENOME-WIDE ASSOCIATION, Polymorphism, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], gene, Biology, 030304 developmental biology, Cancer och onkologi, Population Biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Proportional hazards model, business.industry, Cancers and Neoplasms, Odds ratio, medicine.disease, GENE, Estrogen, susceptibility loci, Minor allele frequency, Cancer and Oncology, FGFR2, genome-wide association, 3111 Biomedicine, business
Abstract

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I-2 = 49.3%; p = less than0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95% CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Published
2012

32. Correction: Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Author

Rebecca Hein, Melanie Maranian, John L. Hopper, Miroslaw K. Kapuscinski, Melissa C. Southey, Daniel J. Park, Marjanka K. Schmidt, Annegien Broeks, Frans B. L. Hogervorst, H. Bas Bueno-de-Mesquit, Kenneth R. Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A. Fasching, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, Roger L. Milne, Jose Ignacio Arias Perez, M. Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A. Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R. Bartram, Rita K. Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, The GENICA Network, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H. Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V. Bogdanova, Iosif V. Zalutsky, Natalia N. Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, kConFab Investigators, AOCS Group, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Zachary Fredericksen, Graham G. Giles, Laura Baglietto, Catriona A. McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M. Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M. John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Jonine D. Figueroa, Montserrat García-Closas, Jolanta Lissowska, Mark E. Sherman, Maartje Hooning, John W. M. Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W. Brock, Simon S. Cross, Malcolm W. R. Reed, Shahana Ahmed, Maya Ghoussaini, Paul DP. Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A. Newcomb, Linda Titus, Kathleen M. Egan, Georgia Chenevix-Trench, Antonis C. Antoniou, Manjeet K. Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F. Easton, and Alison M. Dunning

Subjects
Science, Medicine
Published
2012

33. Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

Author

University of Helsinki, Department of Obstetrics and Gynecology, University of Helsinki, Haartman Institute, University of Helsinki, Clinicum, Sawyer, Elinor, Roylance, Rebecca, Petridis, Christos, Brook, Mark N., Nowinski, Salpie, Papouli, Efterpi, Fletcher, Olivia, Pinder, Sarah, Hanby, Andrew, Kohut, Kelly, Gorman, Patricia, Caneppele, Michele, Peto, Julian, Silva, Isabel dos Santos, Johnson, Nichola, Swann, Ruth, Dwek, Miriam, Perkins, Katherine-Anne, Gillett, Cheryl, Houlston, Richard, Ross, Gillian, De Ieso, Paolo, Southey, Melissa C., Hopper, John L., Provenzano, Elena, Apicella, Carmel, Wesseling, Jelle, Cornelissen, Sten, Keeman, Renske, Fasching, Peter A., Jud, Sebastian M., Ekici, Arif B., Beckmann, Matthias W., Kerin, Michael J., Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guenel, Pascal, Truong, Therese, Laurent-Puig, Pierre, Kerbrat, Pierre, Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Milne, Roger L., Perez, Jose Ignacio Arias, Menendez, Primitiva, Benitez, Javier, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K., Lochmann, Magdalena, Brauch, Hiltrud, Fischer, Hans-Peter, Ko, Yon-Dschun, Nevanlinna, Heli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V., Dork, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Chenevix-Trench, Georgia, Lambrechts, Diether, Weltens, Caroline, Van Limbergen, Erik, Hatse, Sigrid, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Volorio, Sara, Giles, Graham G., Severi, Gianluca, Baglietto, Laura, Mclean, Catriona A., Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark S., Labreche, France, Dumont, Martine, Kristensen, Vessela, Winqvist, Robert, Pylkas, Katri, Jukkola-Vuorinen, Arja, Kauppila, Saila, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Mulligan, Anna Marie, Devillee, Peter, Tollenaar, Rob A. E. M., Seynaeve, Caroline M., Kriege, Mieke, Figueroa, Jonine, Chanock, Stephen J., Sherman, Mark E., Hooning, Maartje J., Hollestelle, Antoinette, van den Ouweland, Ans M. W., van Deurzen, Carolien H. M., Li, Jingmei, Czene, Kamila, Humphreys, Keith, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Shah, Mitul, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Swerdlow, Anthony, Ashworth, Alan, Orr, Nicholas, Schoemaker, Minouk, Couch, Fergus J., Hallberg, Emily, Gonzalez-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Dunning, Alison M., Hall, Per, Easton, Doug, Pharoah, Paul, Schmidt, Marjanka K., Tomlinson, Ian, Garcia-Closas, Montserrat, GENICA Network, KConFab Investigators, University of Helsinki, Department of Obstetrics and Gynecology, University of Helsinki, Haartman Institute, University of Helsinki, Clinicum, Sawyer, Elinor, Roylance, Rebecca, Petridis, Christos, Brook, Mark N., Nowinski, Salpie, Papouli, Efterpi, Fletcher, Olivia, Pinder, Sarah, Hanby, Andrew, Kohut, Kelly, Gorman, Patricia, Caneppele, Michele, Peto, Julian, Silva, Isabel dos Santos, Johnson, Nichola, Swann, Ruth, Dwek, Miriam, Perkins, Katherine-Anne, Gillett, Cheryl, Houlston, Richard, Ross, Gillian, De Ieso, Paolo, Southey, Melissa C., Hopper, John L., Provenzano, Elena, Apicella, Carmel, Wesseling, Jelle, Cornelissen, Sten, Keeman, Renske, Fasching, Peter A., Jud, Sebastian M., Ekici, Arif B., Beckmann, Matthias W., Kerin, Michael J., Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guenel, Pascal, Truong, Therese, Laurent-Puig, Pierre, Kerbrat, Pierre, Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Milne, Roger L., Perez, Jose Ignacio Arias, Menendez, Primitiva, Benitez, Javier, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K., Lochmann, Magdalena, Brauch, Hiltrud, Fischer, Hans-Peter, Ko, Yon-Dschun, Nevanlinna, Heli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V., Dork, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Chenevix-Trench, Georgia, Lambrechts, Diether, Weltens, Caroline, Van Limbergen, Erik, Hatse, Sigrid, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Volorio, Sara, Giles, Graham G., Severi, Gianluca, Baglietto, Laura, Mclean, Catriona A., Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark S., Labreche, France, Dumont, Martine, Kristensen, Vessela, Winqvist, Robert, Pylkas, Katri, Jukkola-Vuorinen, Arja, Kauppila, Saila, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Mulligan, Anna Marie, Devillee, Peter, Tollenaar, Rob A. E. M., Seynaeve, Caroline M., Kriege, Mieke, Figueroa, Jonine, Chanock, Stephen J., Sherman, Mark E., Hooning, Maartje J., Hollestelle, Antoinette, van den Ouweland, Ans M. W., van Deurzen, Carolien H. M., Li, Jingmei, Czene, Kamila, Humphreys, Keith, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Shah, Mitul, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Swerdlow, Anthony, Ashworth, Alan, Orr, Nicholas, Schoemaker, Minouk, Couch, Fergus J., Hallberg, Emily, Gonzalez-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Dunning, Alison M., Hall, Per, Easton, Doug, Pharoah, Paul, Schmidt, Marjanka K., Tomlinson, Ian, Garcia-Closas, Montserrat, GENICA Network, and KConFab Investigators

Published
2014

34. Similarity Measures for Clustering SNP Data

Author

GENICA Network, Ickstadt, Katja, and Selinski, Silvia

Subjects
GENICA, Pearson's Corrected Coefficient of Contingency, single nucleotide polymorphism (SNP), Flexible Matching Coefficient, sporadic breast cancer, similarity, cluster analysis, Matching Coefficient
Abstract

The issue of suitable similarity measures for a particular kind of genetic data – so called SNP data – arises from the GENICA (Interdisciplinary Study Group on Gene Environment Interaction and Breast Cancer in Germany) case-control study of sporadic breast cancer. The GENICA study aims to investigate the influence and interaction of single nucleotide polymorphic (SNP) loci and exogenous risk factors. A single nucleotide polymorphism is a point mutation that is present in at least 1 % of a population. SNPs are the most common form of human genetic variations. In particular, we consider 65 SNP loci and 2 insertions of longer sequences in genes involved in the metabolism of hormones, xenobiotics and drugs as well as in the repair of DNA and signal transduction. Assuming that these single nucleotide changes may lead, for instance, to altered enzymes or to a reduced or enhanced amount of the original enzymes – with each alteration alone having minor effects – we aim to detect combinations of SNPs that under certain environmental conditions increase the risk of sporadic breast cancer. The search for patterns in the present data set may be performed by a variety of clustering and classification approaches. We consider here the problem of suitable measures of proximity of two variables or subjects as an indispensable basis for a further cluster analysis. Generally, clustering approaches are a useful tool to detect structures and to generate hypothesis about potential relationships in complex data situations. Searching for patterns in the data there are two possible objectives: the identification of groups of similar objects or subjects or the identification of groups of similar variables within the whole or within subpopulations. Comparing the individual genetic profiles as well as comparing the genetic information across subpopulations we discuss possible choices of similarity measures, in particular similarity measures based on the counts of matches and mismatches. New matching coefficients are introduced with a more flexible weighting scheme to account for the general problem of the comparison of SNP data: The large proportion of homozygous reference sequences relative to the homo- and heterozygous SNPs is masking the accordances and differences of interest.

Published
2005

35. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.

Author

French, Juliet D, French, Juliet D, Ghoussaini, Maya, Edwards, Stacey L, Meyer, Kerstin B, Michailidou, Kyriaki, Ahmed, Shahana, Khan, Sofia, Maranian, Mel J, O'Reilly, Martin, Hillman, Kristine M, Betts, Joshua A, Carroll, Thomas, Bailey, Peter J, Dicks, Ed, Beesley, Jonathan, Tyrer, Jonathan, Maia, Ana-Teresa, Beck, Andrew, Knoblauch, Nicholas W, Chen, Constance, Kraft, Peter, Barnes, Daniel, González-Neira, Anna, Alonso, M Rosario, Herrero, Daniel, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Luccarini, Craig, Baynes, Caroline, Conroy, Don, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Verhoef, Senno, Cornelissen, Sten, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Loehberg, Christian R, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos Santos Silva, Isabel, Johnson, Nichola, Aitken, Zoe, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Zamora, M Pilar, Arias Perez, Jose Ignacio, Benitez, Javier, Anton-Culver, Hoda, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K, Engel, Christoph, Brauch, Hiltrud, Hamann, Ute, Justenhoven, Christina, GENICA Network, Aaltonen, Kirsimari, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Sueta, Aiko, Bogdanova, Natalia V, Antonenkova, Natalia N, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, French, Juliet D, French, Juliet D, Ghoussaini, Maya, Edwards, Stacey L, Meyer, Kerstin B, Michailidou, Kyriaki, Ahmed, Shahana, Khan, Sofia, Maranian, Mel J, O'Reilly, Martin, Hillman, Kristine M, Betts, Joshua A, Carroll, Thomas, Bailey, Peter J, Dicks, Ed, Beesley, Jonathan, Tyrer, Jonathan, Maia, Ana-Teresa, Beck, Andrew, Knoblauch, Nicholas W, Chen, Constance, Kraft, Peter, Barnes, Daniel, González-Neira, Anna, Alonso, M Rosario, Herrero, Daniel, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Luccarini, Craig, Baynes, Caroline, Conroy, Don, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Verhoef, Senno, Cornelissen, Sten, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Loehberg, Christian R, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos Santos Silva, Isabel, Johnson, Nichola, Aitken, Zoe, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Zamora, M Pilar, Arias Perez, Jose Ignacio, Benitez, Javier, Anton-Culver, Hoda, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K, Engel, Christoph, Brauch, Hiltrud, Hamann, Ute, Justenhoven, Christina, GENICA Network, Aaltonen, Kirsimari, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Sueta, Aiko, Bogdanova, Natalia V, Antonenkova, Natalia N, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, and Kataja, Vesa

Abstract

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

Published
2013

36. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium.

Author

Warren, Helen, Warren, Helen, Dudbridge, Frank, Fletcher, Olivia, Orr, Nick, Johnson, Nichola, Hopper, John L, Apicella, Carmel, Southey, Melissa C, Mahmoodi, Maryam, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Braaf, Linda M, Muir, Kenneth R, Lophatananon, Artitaya, Chaiwerawattana, Arkom, Wiangnon, Surapon, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Schulz-Wendtland, Ruediger, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Mulot, Claire, Bojesen, Stig E, Nielsen, Sune F, Flyger, Henrik, Nordestgaard, Børge G, Milne, Roger L, Benítez, Javier, Arias-Pérez, José-Ignacio, Zamora, M Pilar, Anton-Culver, Hoda, Ziogas, Argyrios, Bernstein, Leslie, Dur, Christina Clarke, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Langheinz, Anne, Meindl, Alfons, Golatta, Michael, Bartram, Claus R, Schmutzler, Rita K, Brauch, Hiltrud, Justenhoven, Christina, Brüning, Thomas, GENICA Network, Chang-Claude, Jenny, Wang-Gohrke, Shan, Eilber, Ursula, Dörk, Thilo, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia, Antonenkova, Natalia, Rogov, Yuriy, Bermisheva, Marina, Prokofyeva, Darya, Zinnatullina, Guzel, Khusnutdinova, Elza, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Hartikainen, Jaana M, Kataja, Vesa, Chenevix-Trench, Georgia, Beesley, Jonathan, Chen, Xiaoqing, kConFab Investigators, Australian Ovarian Cancer Study Group, Lambrechts, Diether, Smeets, Ann, Paridaens, Robert, Weltens, Caroline, Flesch-Janys, Dieter, Buck, Katharina, Behrens, Sabine, Peterlongo, Paolo, Bernard, Loris, Manoukian, Siranoush, Radice, Paolo, Couch, Fergus J, Vachon, Celine, Wang, Xianshu, Olson, Janet, Warren, Helen, Warren, Helen, Dudbridge, Frank, Fletcher, Olivia, Orr, Nick, Johnson, Nichola, Hopper, John L, Apicella, Carmel, Southey, Melissa C, Mahmoodi, Maryam, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Braaf, Linda M, Muir, Kenneth R, Lophatananon, Artitaya, Chaiwerawattana, Arkom, Wiangnon, Surapon, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Schulz-Wendtland, Ruediger, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Mulot, Claire, Bojesen, Stig E, Nielsen, Sune F, Flyger, Henrik, Nordestgaard, Børge G, Milne, Roger L, Benítez, Javier, Arias-Pérez, José-Ignacio, Zamora, M Pilar, Anton-Culver, Hoda, Ziogas, Argyrios, Bernstein, Leslie, Dur, Christina Clarke, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Langheinz, Anne, Meindl, Alfons, Golatta, Michael, Bartram, Claus R, Schmutzler, Rita K, Brauch, Hiltrud, Justenhoven, Christina, Brüning, Thomas, GENICA Network, Chang-Claude, Jenny, Wang-Gohrke, Shan, Eilber, Ursula, Dörk, Thilo, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia, Antonenkova, Natalia, Rogov, Yuriy, Bermisheva, Marina, Prokofyeva, Darya, Zinnatullina, Guzel, Khusnutdinova, Elza, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Hartikainen, Jaana M, Kataja, Vesa, Chenevix-Trench, Georgia, Beesley, Jonathan, Chen, Xiaoqing, kConFab Investigators, Australian Ovarian Cancer Study Group, Lambrechts, Diether, Smeets, Ann, Paridaens, Robert, Weltens, Caroline, Flesch-Janys, Dieter, Buck, Katharina, Behrens, Sabine, Peterlongo, Paolo, Bernard, Loris, Manoukian, Siranoush, Radice, Paolo, Couch, Fergus J, Vachon, Celine, Wang, Xianshu, and Olson, Janet

Abstract

BackgroundOur recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).MethodsTo further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls).ResultsThis replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors.ConclusionsThis study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer.ImpactThe findings further support the view that genetic susceptibility varies according to tumor subtype.

Published
2012

38. Genetic predisposition to in situ and invasive lobular carcinoma of the breast

Author

Sawyer, Elinor, Roylance, Rebecca, Petridis, Christos, Brook, Mark N, Nowinski, Salpie, Papouli, Efterpi, Fletcher, Olivia, Pinder, Sarah, Hanby, Andrew, Kohut, Kelly, Gorman, Patricia, Caneppele, Michele, Peto, Julian, Dos Santos Silva, Isabel, Johnson, Nichola, Swann, Ruth, Dwek, Miriam, Perkins, Katherine-Anne, Gillett, Cheryl, Houlston, Richard, Ross, Gillian, De Ieso, Paolo, Southey, Melissa C, Hopper, John L, Provenzano, Elena, Apicella, Carmel, Wesseling, Jelle, Cornelissen, Sten, Keeman, Renske, Fasching, Peter A, Jud, Sebastian M, Ekici, Arif B, Beckmann, Matthias W, Kerin, Michael J, Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Therese, Laurent-Puig, Pierre, Kerbrat, Pierre, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Benitez, Javier, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K, Lochmann, Magdalena, Brauch, Hiltrud, Fischer, Hans-Peter, Ko, Yon-Dschun, GENICA Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Chenevix-Trench, Georgia, KConFab Investigators, Lambrechts, Diether, Weltens, Caroline, Van Limbergen, Erik, Hatse, Sigrid, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Volorio, Sara, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, McLean, Catriona A, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark S, Labrèche, France, Dumont, Martine, Kristensen, Vessela, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Kauppila, Saila, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Devillee, Peter, Tollenaar, Rob AEM, Seynaeve, Caroline M, Kriege, Mieke, Figueroa, Jonine, Chanock, Stephen J, Sherman, Mark E, Hooning, Maartje J, Hollestelle, Antoinette, Van Den Ouweland, Ans MW, Van Deurzen, Carolien HM, Li, Jingmei, Czene, Kamila, Humphreys, Keith, Cox, Angela, Cross, Simon S, Reed, Malcolm WR, Shah, Mitul, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Swerdlow, Anthony, Ashworth, Alan, Orr, Nicholas, Schoemaker, Minouk, Couch, Fergus J, Hallberg, Emily, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Michailidou, Kyriaki, Dunning, Alison M, Hall, Per, Easton, Doug, Pharoah, Paul, Schmidt, Marjanka K, Tomlinson, Ian, and Garcia-Closas, Montserrat

Subjects
Genotype, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, 3. Good health, body regions, Carcinoma, Lobular, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Carcinoma in Situ, Genome-Wide Association Study
Abstract

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P

39. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author

Kar, Siddhartha P, Beesley, Jonathan, Amin Al Olama, Ali, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, ABCTB Investigators, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, AOCS Study Group & Australian Cancer Study (Ovarian Cancer), APCB BioResource, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, Hopper, John L, Kupryjanczyk, Jolanta, Park, Jong Y, Figueroa, Jonine, Clements, Judith A, Knight, Julia A, Peto, Julian, Cunningham, Julie M, Pow-Sang, Julio, Batra, Jyotsna, Czene, Kamila, Lu, Karen H, Herkommer, Kathleen, Khaw, Kay-Tee, KConFab Investigators, Matsuo, Keitaro, Muir, Kenneth, Offitt, Kenneth, Chen, Kexin, Moysich, Kirsten B, Aittomäki, Kristiina, Odunsi, Kunle, Kiemeney, Lambertus A, Massuger, Leon FAG, Fitzgerald, Liesel M, Cook, Linda S, Cannon-Albright, Lisa, Hooning, Maartje J, Pike, Malcolm C, Bolla, Manjeet K, Luedeke, Manuel, Teixeira, Manuel R, Goodman, Marc T, Schmidt, Marjanka K, Riggan, Marjorie, Aly, Markus, Rossing, Mary Anne, Beckmann, Matthias W, Moisse, Matthieu, Sanderson, Maureen, Southey, Melissa C, Jones, Michael, Lush, Michael, Hildebrandt, Michelle AT, Hou, Ming-Feng, Schoemaker, Minouk J, Garcia-Closas, Montserrat, Bogdanova, Natalia, Rahman, Nazneen, NBCS Investigators, Le, Nhu D, Orr, Nick, Wentzensen, Nicolas, Pashayan, Nora, Peterlongo, Paolo, Guénel, Pascal, Brennan, Paul, Paulo, Paula, Webb, Penelope M, Broberg, Per, Fasching, Peter A, Devilee, Peter, Wang, Qin, Cai, Qiuyin, Li, Qiyuan, Kaneva, Radka, Butzow, Ralf, Kopperud, Reidun Kristin, Schmutzler, Rita K, Stephenson, Robert A, MacInnis, Robert J, Hoover, Robert N, Winqvist, Robert, Ness, Roberta, Milne, Roger L, Travis, Ruth C, Benlloch, Sara, Olson, Sara H, McDonnell, Shannon K, Tworoger, Shelley S, Maia, Sofia, Berndt, Sonja, Lee, Soo Chin, Teo, Soo-Hwang, Thibodeau, Stephen N, Bojesen, Stig E, Gapstur, Susan M, Kjær, Susanne Krüger, Pejovic, Tanja, Tammela, Teuvo LJ, GENICA Network, PRACTICAL Consortium, Dörk, Thilo, Brüning, Thomas, Wahlfors, Tiina, Key, Tim J, Edwards, Todd L, Menon, Usha, Hamann, Ute, Mitev, Vanio, Kosma, Veli-Matti, Setiawan, Veronica Wendy, Kristensen, Vessela, Arndt, Volker, Vogel, Walther, Zheng, Wei, Sieh, Weiva, Blot, William J, Kluzniak, Wojciech, Shu, Xiao-Ou, Gao, Yu-Tang, Schumacher, Fredrick, Freedman, Matthew L, Berchuck, Andrew, Dunning, Alison M, Simard, Jacques, Haiman, Christopher A, Spurdle, Amanda, Sellers, Thomas A, Hunter, David J, Henderson, Brian E, Kraft, Peter, Chanock, Stephen J, Couch, Fergus J, Hall, Per, Gayther, Simon A, Easton, Douglas F, Chenevix-Trench, Georgia, Eeles, Rosalind, Pharoah, Paul DP, and Lambrechts, Diether

Subjects
Male, Ovarian Neoplasms, Quantitative Trait Loci, Chromosome Mapping, Datasets as Topic, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, 3. Good health, Enhancer Elements, Genetic, Meta-Analysis as Topic, Genetic Loci, Organ Specificity, Case-Control Studies, Humans, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Signal Transduction
Abstract

UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

40. An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Author

Wyszynski, Asaf, Hong, Chi-Chen, Lam, Kristin, Michailidou, Kyriaki, Lytle, Christian, Yao, Song, Zhang, Yali, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Nordestgaard, Børge G, González-Neira, Anna, Benitez, Javier, Neuhausen, Susan L, Brenner, Hermann, Dieffenbach, Aida Karina, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, GENICA Network, Nevanlinna, Heli, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Dörk, Thilo, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, KConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Van Den Berg, David, Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Peterlongo, Paolo, Couch, Fergus J, Olson, Janet E, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Henderson, Brian E, Dumont, Martine, Teo, Soo Hwang, Wong, Tien Y, Kristensen, Vessela, Zheng, Wei, Long, Jirong, Winqvist, Robert, Pylkäs, Katri, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Seynaeve, Caroline, García-Closas, Montserrat, Figueroa, Jonine, Klevebring, Daniel, Czene, Kamila, Hooning, Maartje J, Van Den Ouweland, Ans MW, Darabi, Hatef, Shu, Xiao-Ou, Gao, Yu-Tang, Cox, Angela, Blot, William, Signorello, Lisa B, Shah, Mitul, Kang, Daehee, Choi, Ji-Yeob, Hartman, Mikael, Miao, Hui, Hamann, Ute, Jakubowska, Anna, Lubinski, Jan, Sangrajrang, Suleeporn, McKay, James, Toland, Amanda E, Yannoukakos, Drakoulis, Shen, Chen-Yang, Wu, Pei-Ei, Swerdlow, Anthony, Orr, Nick, Simard, Jacques, Pharoah, Paul DP, Dunning, Alison M, Chenevix-Trench, Georgia, Hall, Per, Bandera, Elisa, Amos, Chris, Ambrosone, Christine, Easton, Douglas F, and Cole, Michael D

Subjects
Adult, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, 3. Good health, Gene Expression Regulation, Neoplastic, Young Adult, Enhancer Elements, Genetic, Case-Control Studies, Chromosomes, Human, Pair 2, MCF-7 Cells, Humans, Female, Genetic Predisposition to Disease, Carrier Proteins, Insulin-Like Growth Factor Binding Protein 5, Promoter Regions, Genetic, Aged, Sequence Deletion
Abstract

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

41. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author

Perry, John Rb, Day, Felix, Elks, Cathy E, Sulem, Patrick, Thompson, Deborah J, Ferreira, Teresa, He, Chunyan, Chasman, Daniel I, Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q, Corre, Tanguy, Cousminer, Diana L, Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D, Kjellqvist, Sanela, Lunetta, Kathryn L, McMahon, George, Nolte, Ilja M, Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K, Amin, Najaf, Bierut, Laura J, Byrne, Enda M, Hottenga, Jouke-Jan, Koller, Daniel L, Mangino, Massimo, Pers, Tune H, Yerges-Armstrong, Laura M, Zhao, Jing Hua, Andrulis, Irene L, Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E, Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collée, J Margriet, Couch, Fergus J, Couper, David, Coveillo, Andrea D, Cox, Angela, Czene, Kamila, D'adamo, Adamo Pio, Smith, George Davey, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K, Dunning, Alison M, Eiriksdottir, Gudny, Eriksson, Johan G, Fasching, Peter A, Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E, García-Closas, Montserrat, Geller, Frank, De Geus, Eco Ej, Giles, Graham G, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A, Heath, Andrew C, Hofman, Albert, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Hunter, David J, Karasik, David, Kiel, Douglas P, Knight, Julia A, Kosma, Veli-Matti, Kutalik, Zoltan, Lai, Sandra, Lambrechts, Diether, Lindblom, Annika, Mägi, Reedik, Magnusson, Patrik K, Mannermaa, Arto, Martin, Nicholas G, Masson, Gisli, McArdle, Patrick F, McArdle, Wendy L, Melbye, Mads, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L, Nevanlinna, Heli, Neven, Patrick, Nohr, Ellen A, Oldehinkel, Albertine J, Oostra, Ben A, Palotie, Aarno, Peacock, Munro, Pedersen, Nancy L, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul Dp, Postma, Dirkje S, Pouta, Anneli, Pylkäs, Katri, Radice, Paolo, Ring, Susan, Rivadeneira, Fernando, Robino, Antonietta, Rose, Lynda M, Rudolph, Anja, Salomaa, Veikko, Sanna, Serena, Schlessinger, David, Schmidt, Marjanka K, Southey, Mellissa C, Sovio, Ulla, Stampfer, Meir J, Stöckl, Doris, Storniolo, Anna M, Timpson, Nicholas J, Tyrer, Jonathan, Visser, Jenny A, Vollenweider, Peter, Völzke, Henry, Waeber, Gerard, Waldenberger, Melanie, Wallaschofski, Henri, Wang, Qin, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce Hr, Wright, Margaret J, Australian Ovarian Cancer Study, GENICA Network, KConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, Boomsma, Dorret I, Econs, Michael J, Khaw, Kay-Tee, Loos, Ruth Jf, McCarthy, Mark I, Montgomery, Grant W, Rice, John P, Streeten, Elizabeth A, Thorsteinsdottir, Unnur, Van Duijn, Cornelia M, Alizadeh, Behrooz Z, Bergmann, Sven, Boerwinkle, Eric, Boyd, Heather A, Crisponi, Laura, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kraft, Peter, Lawlor, Debbie, Metspalu, Andres, Pennell, Craig E, Ridker, Paul M, Snieder, Harold, Sørensen, Thorkild Ia, Spector, Tim D, Strachan, David P, Uitterlinden, André G, Wareham, Nicholas J, Widen, Elisabeth, Zygmunt, Marek, Murray, Anna, Easton, Douglas F, Stefansson, Kari, Murabito, Joanne M, and Ong, Ken K

Subjects
Male, Parents, Hypothalamo-Hypophyseal System, Adolescent, Receptors, Retinoic Acid, Ubiquitin-Protein Ligases, Quantitative Trait Loci, Breast Neoplasms, Polymorphism, Single Nucleotide, Body Mass Index, Genomic Imprinting, Potassium Channels, Tandem Pore Domain, Humans, Obesity, Child, Alleles, 2. Zero hunger, Menarche, Calcium-Binding Proteins, Ovary, Age Factors, Membrane Proteins, Proteins, 3. Good health, Europe, Diabetes Mellitus, Type 2, Receptors, GABA-B, Ribonucleoproteins, Cardiovascular Diseases, Genetic Loci, Intercellular Signaling Peptides and Proteins, Female, Genome-Wide Association Study
Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

42. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Author

Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Torres, Diana, Purrington, Kristen S., Slettedahl, Seth, Bolla, Manjeet K., Michailidou, Kyriaki, Czene, Kamila, Nevanlinna, Heli, Bojesen, Stig E., Andrulis, Irene L., Cox, Angela, Hall, Per, Carpenter, Jane, Yannoukakos, Drakoulis, Haiman, Christopher A., Fasching, Peter A., Mannermaa, Arto, Winqvist, Robert, Brenner, Hermann, Lindblom, Annika, Chenevix-Trench, Georgia, Benitez, Javier, Swerdlow, Anthony, Kristensen, Vessela, Guenel, Pascal, Meindl, Alfons, Darabi, Hatef, Eriksson, Mikael, Fagerholm, Rainer, Aittomaki, Kristiina, Blomqvist, Carl, Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Wang, Xianshu, Olswold, Curtis, Olson, Janet E., Mulligan, Anna Marie, Knight, Julia A., Tchatchou, Sandrine, Reed, Malcolm W. R., Cross, Simon S., Liu, Jianjun, Li, Jingmei, Humphreys, Keith, Clarke, Christine, Scott, Rodney, Fostira, Florentia, Fountzilas, George, Konstantopoulou, Irene, Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Ekici, Arif B., Hartmann, Arndt, Beckmann, Matthias W., Hartikainen, Jaana M., Kosma, Veli-Matti, Kataja, Vesa, Jukkola-Vuorinen, Arja, Pylkas, Katri, Kauppila, Saila, Dieffenbach, Aida Karina, Stegmaier, Christa, Arndt, Volker, Margolin, Sara, Balleine, Rosemary, Arias Perez, Jose Ignacio, Pilar Zamora, M., Menendez, Primitiva, Ashworth, Alan, Jones, Michael, Orr, Nick, Arveux, Patrick, Kerbrat, Pierre, Therese Truong, Bugert, Peter, Toland, Amanda E., Ambrosone, Christine B., Labreche, France, Goldberg, Mark S., Dumont, Martine, Ziogas, Argyrios, Lee, Eunjung, Dite, Gillian S., Apicella, Carmel, Southey, Melissa C., Long, Jirong, Shrubsole, Martha, Deming-Halverson, Sandra, Ficarazzi, Filomena, Barile, Monica, Peterlongo, Paolo, Durda, Katarzyna, Jaworska Bieniek, Katarzyna, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Ko, Yon Dschun, Van Deurzen, Carolien H. M., Martens, John W. M., Kriege, Mieke, Figueroa, Jonine D., Chanock, Stephen J., Lissowska, Jolanta, Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Schneeweiss, Andreas, Tapper, William J., Gerty, Susan M., Durcan, Lorraine, Mclean, Catriona, Milne, Roger L., Baglietto, Laura, Silva, Isabel dos Santos, Fletcher, Olivia, Johnson, Nichola, Van'T Veer, Laura J., Cornelissen, Sten, Rudolph, Anja, Flesch-Janys, Dieter, Nickels, Stefan, Weltens, Caroline, Floris, Giuseppe, Moisse, Matthieu, Dennis, Joe, Wang, Qin, Dunning, Alison M., Shah, Mitul, Brown, Judith, Simard, Jacques, Anton-Culver, Hoda, Neuhausen, Susan L., Hopper, John L., Bogdanova, Natalia, Doerk, Thilo, Zheng, Wei, Radice, Paolo, Jakubowska, Anna, Lubinski, Jan, Devillee, Peter, Brauch, Hiltrud, Hooning, Maartje, Garcia Closas, Montserrat, Sawyer, Elinor, Burwinkel, Barbara, Marmee, Frederick, Eccles, Diana M., Giles, Graham G., Peto, Julian, Schmidt, Marjanka, Broeks, Annegien, Hamann, Ute, Lambrechts, Diether, Chang Claude, Jenny, Pharoah, Paul D. P., Easton, Douglas, Pankratz, V. Shane, Slager, Susan, Vachon, Celine M., Couch, Fergus J., Försti, Asta, ABCTB Investigators, Australian Ovarian Cancer Study Group, kConFab Investigators, The GENICA Network, Brüning, Thomas, Rüdiger, Thomas, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Torres, Diana, Purrington, Kristen S., Slettedahl, Seth, Bolla, Manjeet K., Michailidou, Kyriaki, Czene, Kamila, Nevanlinna, Heli, Bojesen, Stig E., Andrulis, Irene L., Cox, Angela, Hall, Per, Carpenter, Jane, Yannoukakos, Drakoulis, Haiman, Christopher A., Fasching, Peter A., Mannermaa, Arto, Winqvist, Robert, Brenner, Hermann, Lindblom, Annika, Chenevix-Trench, Georgia, Benitez, Javier, Swerdlow, Anthony, Kristensen, Vessela, Guenel, Pascal, Meindl, Alfons, Darabi, Hatef, Eriksson, Mikael, Fagerholm, Rainer, Aittomaki, Kristiina, Blomqvist, Carl, Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Wang, Xianshu, Olswold, Curtis, Olson, Janet E., Mulligan, Anna Marie, Knight, Julia A., Tchatchou, Sandrine, Reed, Malcolm W. R., Cross, Simon S., Liu, Jianjun, Li, Jingmei, Humphreys, Keith, Clarke, Christine, Scott, Rodney, Fostira, Florentia, Fountzilas, George, Konstantopoulou, Irene, Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Ekici, Arif B., Hartmann, Arndt, Beckmann, Matthias W., Hartikainen, Jaana M., Kosma, Veli-Matti, Kataja, Vesa, Jukkola-Vuorinen, Arja, Pylkas, Katri, Kauppila, Saila, Dieffenbach, Aida Karina, Stegmaier, Christa, Arndt, Volker, Margolin, Sara, Balleine, Rosemary, Arias Perez, Jose Ignacio, Pilar Zamora, M., Menendez, Primitiva, Ashworth, Alan, Jones, Michael, Orr, Nick, Arveux, Patrick, Kerbrat, Pierre, Therese Truong, Bugert, Peter, Toland, Amanda E., Ambrosone, Christine B., Labreche, France, Goldberg, Mark S., Dumont, Martine, Ziogas, Argyrios, Lee, Eunjung, Dite, Gillian S., Apicella, Carmel, Southey, Melissa C., Long, Jirong, Shrubsole, Martha, Deming-Halverson, Sandra, Ficarazzi, Filomena, Barile, Monica, Peterlongo, Paolo, Durda, Katarzyna, Jaworska Bieniek, Katarzyna, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Ko, Yon Dschun, Van Deurzen, Carolien H. M., Martens, John W. M., Kriege, Mieke, Figueroa, Jonine D., Chanock, Stephen J., Lissowska, Jolanta, Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Schneeweiss, Andreas, Tapper, William J., Gerty, Susan M., Durcan, Lorraine, Mclean, Catriona, Milne, Roger L., Baglietto, Laura, Silva, Isabel dos Santos, Fletcher, Olivia, Johnson, Nichola, Van'T Veer, Laura J., Cornelissen, Sten, Rudolph, Anja, Flesch-Janys, Dieter, Nickels, Stefan, Weltens, Caroline, Floris, Giuseppe, Moisse, Matthieu, Dennis, Joe, Wang, Qin, Dunning, Alison M., Shah, Mitul, Brown, Judith, Simard, Jacques, Anton-Culver, Hoda, Neuhausen, Susan L., Hopper, John L., Bogdanova, Natalia, Doerk, Thilo, Zheng, Wei, Radice, Paolo, Jakubowska, Anna, Lubinski, Jan, Devillee, Peter, Brauch, Hiltrud, Hooning, Maartje, Garcia Closas, Montserrat, Sawyer, Elinor, Burwinkel, Barbara, Marmee, Frederick, Eccles, Diana M., Giles, Graham G., Peto, Julian, Schmidt, Marjanka, Broeks, Annegien, Hamann, Ute, Lambrechts, Diether, Chang Claude, Jenny, Pharoah, Paul D. P., Easton, Douglas, Pankratz, V. Shane, Slager, Susan, Vachon, Celine M., Couch, Fergus J., Försti, Asta, ABCTB Investigators, Australian Ovarian Cancer Study Group, kConFab Investigators, The GENICA Network, Brüning, Thomas, and Rüdiger, Thomas

43. Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating map3k1

Author

Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Glubb, Dylan M., Maranian, Mel J., Michailidou, Kyriaki, Pooley, Karen A., Meyer, Kerstin B., Kar, Siddhartha, Carlebur, Saskia, O'Reilly, Martin, Betts, Joshua A., Hillman, Kristine M., Kaufmann, Susanne, Beesley, Jonathan, Canisius, Sander, Hopper, John L., Southey, Melissa C., Tsimiklis, Helen, Apicella, Carmel, Schmidt, Marjanka K., Broeks, Annegien, Hogervorst, Frans B., van der Schoot, C. Ellen, Muir, Kenneth, Lophatananon, Artitaya, Stewart Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A., Ruebner, Matthias, Ekici, Arif B., Beckmann, Matthias W., Peto, Julian, Dos Santos Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Pharoah, Paul D. P., Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Yang, Rongxi, Surowy, Harald, Guenel, Pascal, Truong, Therese, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Gonzalez Neira, Anna, Benitez, Javier, Pilar Zamora, M., Arias Perez, Jose Ignacio, Anton Culver, Hoda, Neuhausen, Susan L., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud, Ko, Yon Dschun, Bruening, Thomas, Nevanlinna, Heli, Muranen, Taru A., Aittomaeki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tanaka, Hideo, Doerk, Thilo, Bogdanova, Natalia V., Helbig, Sonja, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli Matti, Hartikainen, Jaana M., Wu, Anna H., Tseng, Chiu chen, Van den Berg, David, Stram, Daniel O., Lambrechts, Diether, Zhao, Hui, Weltens, Caroline, van Limbergen, Erik, Chang Claude, Jenny, Flesch Janys, Dieter, Rudolph, Anja, Seibold, Petra, Radice, Paolo, Peterlongo, Paolo, Barile, Monica, Capra, Fabio, Couch, Fergus J., Olson, Janet E., Hallberg, Emily, Vachon, Celine, Giles, Graham G., Milne, Roger L., McLean, Catriona, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark S., Labreche, France, Dumont, Martine, Teo, Soo Hwang, Yip, Cheng Har, See, Mee Hoong, Cornes, Belinda, Cheng, Ching Yu, Ikram, M. Kamran, Kristensen, Vessela, Zheng, Wei, Halverson, Sandra L., Shrubsole, Martha, Long, Jirong, Winqvist, Robert, Pylkaes, Katri, Jukkola Vuorinen, Arja, Kauppila, Saila, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Van Asperen, Christi J., Garcia Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J., Lissowska, Jolanta, Czene, Kamila, Klevebring, Daniel, Darabi, Hatef, Eriksson, Mikael, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W. M., Collee, J. Margriet, Hall, Per, Li, Jingmei, Humphreys, Keith, Shu, Xiao Ou, Lu, Wei, Gao, Yu Tang, Cai, Hui, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Blot, William, Signorello, Lisa B., Cai, Qiuyin, Shah, Mitul, Ghoussaini, Maya, Kang, Daehee, Choi, Ji Yeob, Park, Sue K., Noh, Dong Young, Hartman, Mikael, Miao, Hui, Lim, Wei Yen, Tang, Anthony, Hamann, Ute, Tórres López, Diana María, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Sangrajrang, Suleeporn, Gaborieau, Valerie, Brennan, Paul, McKay, James, Olswold, Curtis, Slager, Susan, Toland, Amanda E., Yannoukakos, Drakoulis, Shen, Chen Yang, Wu, Pei Ei, Yu, Jyh Cherng, Hou, Ming Feng, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, Pita, Guillermo, Rosario Alonso, M., Alvarez, Nuria, Herrero, Daniel, Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Luccarini, Craig, Baynes, Caroline, Ahmed, Shahana, Healey, Catherine S., Brown, Melissa A., Ponder, Bruce A. J., Chenevix Trench, Georgia, Thompson, Deborah J., Edwards, Stacey L., Easton, Douglas F., Dunning, Alison M., French, Juliet D., The GENICA Network, kConFab Investigators, Norwegian Breast Cancer Study, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Glubb, Dylan M., Maranian, Mel J., Michailidou, Kyriaki, Pooley, Karen A., Meyer, Kerstin B., Kar, Siddhartha, Carlebur, Saskia, O'Reilly, Martin, Betts, Joshua A., Hillman, Kristine M., Kaufmann, Susanne, Beesley, Jonathan, Canisius, Sander, Hopper, John L., Southey, Melissa C., Tsimiklis, Helen, Apicella, Carmel, Schmidt, Marjanka K., Broeks, Annegien, Hogervorst, Frans B., van der Schoot, C. Ellen, Muir, Kenneth, Lophatananon, Artitaya, Stewart Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A., Ruebner, Matthias, Ekici, Arif B., Beckmann, Matthias W., Peto, Julian, Dos Santos Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Pharoah, Paul D. P., Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Sawyer, Elinor J., Tomlinson, Ian, Kerin, Michael J., Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Yang, Rongxi, Surowy, Harald, Guenel, Pascal, Truong, Therese, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Gonzalez Neira, Anna, Benitez, Javier, Pilar Zamora, M., Arias Perez, Jose Ignacio, Anton Culver, Hoda, Neuhausen, Susan L., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud, Ko, Yon Dschun, Bruening, Thomas, Nevanlinna, Heli, Muranen, Taru A., Aittomaeki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tanaka, Hideo, Doerk, Thilo, Bogdanova, Natalia V., Helbig, Sonja, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli Matti, Hartikainen, Jaana M., Wu, Anna H., Tseng, Chiu chen, Van den Berg, David, Stram, Daniel O., Lambrechts, Diether, Zhao, Hui, Weltens, Caroline, van Limbergen, Erik, Chang Claude, Jenny, Flesch Janys, Dieter, Rudolph, Anja, Seibold, Petra, Radice, Paolo, Peterlongo, Paolo, Barile, Monica, Capra, Fabio, Couch, Fergus J., Olson, Janet E., Hallberg, Emily, Vachon, Celine, Giles, Graham G., Milne, Roger L., McLean, Catriona, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark S., Labreche, France, Dumont, Martine, Teo, Soo Hwang, Yip, Cheng Har, See, Mee Hoong, Cornes, Belinda, Cheng, Ching Yu, Ikram, M. Kamran, Kristensen, Vessela, Zheng, Wei, Halverson, Sandra L., Shrubsole, Martha, Long, Jirong, Winqvist, Robert, Pylkaes, Katri, Jukkola Vuorinen, Arja, Kauppila, Saila, Andrulis, Irene L., Knight, Julia A., Glendon, Gord, Tchatchou, Sandrine, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Van Asperen, Christi J., Garcia Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J., Lissowska, Jolanta, Czene, Kamila, Klevebring, Daniel, Darabi, Hatef, Eriksson, Mikael, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W. M., Collee, J. Margriet, Hall, Per, Li, Jingmei, Humphreys, Keith, Shu, Xiao Ou, Lu, Wei, Gao, Yu Tang, Cai, Hui, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Blot, William, Signorello, Lisa B., Cai, Qiuyin, Shah, Mitul, Ghoussaini, Maya, Kang, Daehee, Choi, Ji Yeob, Park, Sue K., Noh, Dong Young, Hartman, Mikael, Miao, Hui, Lim, Wei Yen, Tang, Anthony, Hamann, Ute, Tórres López, Diana María, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Sangrajrang, Suleeporn, Gaborieau, Valerie, Brennan, Paul, McKay, James, Olswold, Curtis, Slager, Susan, Toland, Amanda E., Yannoukakos, Drakoulis, Shen, Chen Yang, Wu, Pei Ei, Yu, Jyh Cherng, Hou, Ming Feng, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, Pita, Guillermo, Rosario Alonso, M., Alvarez, Nuria, Herrero, Daniel, Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Luccarini, Craig, Baynes, Caroline, Ahmed, Shahana, Healey, Catherine S., Brown, Melissa A., Ponder, Bruce A. J., Chenevix Trench, Georgia, Thompson, Deborah J., Edwards, Stacey L., Easton, Douglas F., Dunning, Alison M., French, Juliet D., The GENICA Network, kConFab Investigators, and Norwegian Breast Cancer Study

44. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Author

Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Hollestelle, Antoinette, van der Baan, Frederieke H., Berchuck, Andrew, Johnatty, Sharon E., Aben, Katja K., Agnarsson, Bjarni A., Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Antoniou, Antonis C., Apicella, Carmel, Arndt, Volker, Arnold, Norbert, Arun, Banu K., Arver, Brita, Ashworth, Alan, Australian Ovarian Cancer Study Group, Baglietto, Laura, Balleine, Rosemary, Bandera, Elisa V., Barrowdale, Daniel, Bean, Yukie T., Beckmann, Lars, Beckmann, Matthias W., Benitez, Javier, Berger, Andreas, Berger, Raanan, Beuselinck, Benoit, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Brand, Judith S., Brauch, Hiltrud, Breast Cancer Family Register, Brenner, Hermann, Brinton, Louise, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Brüning, Thomas, Budzilowska, Agnieszka, Bunker, Clareann H., Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S., Caligo, Maria A., Campbell, Ian, Carter, Jonathan, Chang-Claude, Jenny, Chanock, Stephen J., M. Claes, Kathleen B., Collée, J. Margriet, Cook, Linda S., Couch, Fergus J., Cox, Angela, Cramer, Daniel, Cross, Simon S., Cunningham, Julie M., Cybulski, Cezary, Czene, Kamila, Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, de la Hoya, Miguel, de Fazio, Anna, Dennis, Joseph, Devilee, Peter, Dicks, Ed M., Diez, Orland, Doherty, Jennifer A., Domchek, Susan M., Dorfling, Cecilia M., Dörk, Thilo, Dos Santos Silva, Isabel, du Bois, Andreas, Dumont, Martine, Dunning, Alison M., Duran, Mercedes, Easton, Douglas F., Eccles, Diana, Edwards, Robert P., Ehrencrona, Hans, Ejlertsen, Bent, Ekici, Arif B., Ellis, Steve D., EMBRACE, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Fontaine, Annette, Fortuzzi, Stefano, Fostira, Florentia, Fridley, Brooke L., Friebel, Tara, Friedman, Eitan, Friel, Grace, Frost, Debra, Garbe, Judy, García-Closas, Montserrat, Gayther, Simon A., GEMO Study Collaborators, GENICA Network, Gentry-Maharaj, Aleksandra, Anne-Marie, Gerdes, Giles, Graham G., Glasspool, Rosalind, Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Gore, Martin, Greene, Mark H., Grip, Mervi, Gronwald, Jacek, Gschwantler Kaulich, Daphne, Guénel, Pascal, Guzman, Starr R., Haeberle, Lothar, Haiman, Christopher A., Hall, Per, Halverson, Sandra L., Hamann, Ute, O. Hansen, Thomas V., Harter, Philipp, Hartikainen, Jaana M., Healey, Sue, HEBON, Hein, Alexander, Heitz, Florian, Henderson, Brian E., Herzog, Josef, T Hildebrandt, Michelle A., Høgdall, Claus K., Høgdall, Estrid, L. Hogervorst, Frans B., Hopper, John L., Humphreys, Keith, Huzarski, Tomasz, Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska, Katarzyna, Jensen, Allan, Birk Jensen, Uffe, Johnson, Nichola, Jukkola-Vuorinen, Arja, Kabisch, Maria, Karlan, Beth Y., Kataja, Vesa, Kauff, Noah, KConFab Investigators, Kelemen, Linda E., Kerin, Michael J., Kiemeney, Lambertus A., Kjaer, Susanne K., Knight, Julia A., Knol-Bout, Jacoba P., Konstantopoulou, Irene, Kosma, Veli-Matti, Krakstad, Camilla, Kristensen, Vessela, Kuchenbaecker, Karoline B., Kupryjanczyk, Jolanta, Laitman, Yael, Lambrechts, Diether, Lambrechts, Sandrina, Larson, Melissa C., Lasa, Adriana, Laurent-Puig, Pierre, Lazaro, Conxi, Le, Nhu D., Le Marchand, Loic, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Li, Jingmei, Liang, Dong, Lindblom, Annika, Lindor, Noralane, Lissowska, Jolanta, Long, Jirong, Lu, Karen H., Lubinski, Jan, Lundvall, Lene, Lurie, Galina, Mai, Phuong L., Mannermaa, Arto, Margolin, Sara, Mariette, Frederique, Marme, Frederik, M. Martens, John W., G. Massuger, Leon F.A., Maugard, Christine, Mazoyer, Sylvie, McGuffog, Lesley, McGuire, Valerie, McLean, Catriona, McNeish, Iain, Meindl, Alfons, Menegaux, Florence, Menéndez, Primitiva, Menkiszak, Janusz, Menon, Usha, Mensenkamp, Arjen R., Miller, Nicola, Milne, Roger L., Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Müller, Heiko, Mulligan, Anna Marie, Muranen, Taru A., Narod, Steven A., Nathanson, Katherine L., Ness, Roberta B., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Nielsen, Finn C., Nielsen, Sune F., Nordestgaard, Børge G., Nussbaum, Robert L., Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olson, Sara H., Oosterwijk, Jan C., Orlow, Irene, Orr, Nick, Orsulic, Sandra, Osorio, Ana, Ottini, Laura, Paul, James, Pearce, Celeste L., Sokilde Pedersen, Inge, Peissel, Bernard, Pejovic, Tanja, Pelttari, Liisa M., Perkins, Jo, Permuth-Wey, Jenny, Peterlongo, Paolo, Peto, Julian, Phelan, Catherine M., Phillips, Kelly-Anne, Piedmonte, Marion, Pike, Malcolm C., Platte, Radka, Plisiecka-Halasa, Joanna, Poole, Elizabeth M., Poppe, Bruce, Pylkäs, Katri, Radice, Paolo, Ramus, Susan J., Rebbeck, Timothy R., R. Reed, Malcolm W., Rennert, Gad, Risch, Harvey A., Robson, Mark, Rodriguez, Gustavo C., Romero, Atocha, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo, Salani, Ritu, Salvesen, Helga B., Sawyer, Elinor J., Schildkraut, Joellen M., Schmidt, Marjanka K., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schrauder, Michael G., Schumacher, Fredrick, Schwaab, Ira, Scuvera, Giulietta, Sellers, Thomas A., Severi, Gianluca, Seynaeve, Caroline M., Shah, Mitul, Shrubsole, Martha, Siddiqui, Nadeem, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sinilnikova, Olga M., Smeets, Dominiek, Sohn, Christof, Soller, Maria, Song, Honglin, Soucy, Penny, Southey, Melissa C., Stegmaier, Christa, Stoppa-Lyonnet, Dominique, Sucheston, Lara, SWE-BRCA, Swerdlow, Anthony, Tangen, Ingvild L., Tea, Muy-Kheng, Teixeira, Manuel R., Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Tihomirova, Laima, Tischkowitz, Marc, Ewart Toland, Amanda, M. Tollenaar, Rob A.E., Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Tsimiklis, Helen, Tung, Nadine, Tworoger, Shelley S., Tyrer, Jonathan P., Vachon, Celine M., Van 't Veer, Laura J., van Altena, Anne M., Van Asperen, C.J., van den Berg, David, van den Ouweland, Ans M.W., van Doorn, Helena C., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vergote, Ignace, Verhoef, Senno, Vierkant, Robert A., Vijai, Joseph, Vitonis, Allison F., von Wachenfeldt, Anna, Walsh, Christine, Wang, Qin, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weischer, Maren, Weitzel, Jeffrey N., Weltens, Caroline, Wentzensen, Nicolas, Whittemore, Alice S., Wilkens, Lynne R., Winqvist, Robert, Wu, Anna H., Wu, Xifeng, Yang, Hannah P., Zaffaroni, Daniela, Zamora, M. Pilar, Zheng, Wei, Ziogas, Argyrios, Chenevix-Trench, Georgia, P. Pharoah, Paul D., Rookus, Matti A., Hooning, Maartje J., Goode, Ellen L., Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Hollestelle, Antoinette, van der Baan, Frederieke H., Berchuck, Andrew, Johnatty, Sharon E., Aben, Katja K., Agnarsson, Bjarni A., Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Antoniou, Antonis C., Apicella, Carmel, Arndt, Volker, Arnold, Norbert, Arun, Banu K., Arver, Brita, Ashworth, Alan, Australian Ovarian Cancer Study Group, Baglietto, Laura, Balleine, Rosemary, Bandera, Elisa V., Barrowdale, Daniel, Bean, Yukie T., Beckmann, Lars, Beckmann, Matthias W., Benitez, Javier, Berger, Andreas, Berger, Raanan, Beuselinck, Benoit, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Brand, Judith S., Brauch, Hiltrud, Breast Cancer Family Register, Brenner, Hermann, Brinton, Louise, Brooks-Wilson, Angela, Bruinsma, Fiona, Brunet, Joan, Brüning, Thomas, Budzilowska, Agnieszka, Bunker, Clareann H., Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S., Caligo, Maria A., Campbell, Ian, Carter, Jonathan, Chang-Claude, Jenny, Chanock, Stephen J., M. Claes, Kathleen B., Collée, J. Margriet, Cook, Linda S., Couch, Fergus J., Cox, Angela, Cramer, Daniel, Cross, Simon S., Cunningham, Julie M., Cybulski, Cezary, Czene, Kamila, Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, de la Hoya, Miguel, de Fazio, Anna, Dennis, Joseph, Devilee, Peter, Dicks, Ed M., Diez, Orland, Doherty, Jennifer A., Domchek, Susan M., Dorfling, Cecilia M., Dörk, Thilo, Dos Santos Silva, Isabel, du Bois, Andreas, Dumont, Martine, Dunning, Alison M., Duran, Mercedes, Easton, Douglas F., Eccles, Diana, Edwards, Robert P., Ehrencrona, Hans, Ejlertsen, Bent, Ekici, Arif B., Ellis, Steve D., EMBRACE, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Fontaine, Annette, Fortuzzi, Stefano, Fostira, Florentia, Fridley, Brooke L., Friebel, Tara, Friedman, Eitan, Friel, Grace, Frost, Debra, Garbe, Judy, García-Closas, Montserrat, Gayther, Simon A., GEMO Study Collaborators, GENICA Network, Gentry-Maharaj, Aleksandra, Anne-Marie, Gerdes, Giles, Graham G., Glasspool, Rosalind, Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Gore, Martin, Greene, Mark H., Grip, Mervi, Gronwald, Jacek, Gschwantler Kaulich, Daphne, Guénel, Pascal, Guzman, Starr R., Haeberle, Lothar, Haiman, Christopher A., Hall, Per, Halverson, Sandra L., Hamann, Ute, O. Hansen, Thomas V., Harter, Philipp, Hartikainen, Jaana M., Healey, Sue, HEBON, Hein, Alexander, Heitz, Florian, Henderson, Brian E., Herzog, Josef, T Hildebrandt, Michelle A., Høgdall, Claus K., Høgdall, Estrid, L. Hogervorst, Frans B., Hopper, John L., Humphreys, Keith, Huzarski, Tomasz, Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska, Katarzyna, Jensen, Allan, Birk Jensen, Uffe, Johnson, Nichola, Jukkola-Vuorinen, Arja, Kabisch, Maria, Karlan, Beth Y., Kataja, Vesa, Kauff, Noah, KConFab Investigators, Kelemen, Linda E., Kerin, Michael J., Kiemeney, Lambertus A., Kjaer, Susanne K., Knight, Julia A., Knol-Bout, Jacoba P., Konstantopoulou, Irene, Kosma, Veli-Matti, Krakstad, Camilla, Kristensen, Vessela, Kuchenbaecker, Karoline B., Kupryjanczyk, Jolanta, Laitman, Yael, Lambrechts, Diether, Lambrechts, Sandrina, Larson, Melissa C., Lasa, Adriana, Laurent-Puig, Pierre, Lazaro, Conxi, Le, Nhu D., Le Marchand, Loic, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Li, Jingmei, Liang, Dong, Lindblom, Annika, Lindor, Noralane, Lissowska, Jolanta, Long, Jirong, Lu, Karen H., Lubinski, Jan, Lundvall, Lene, Lurie, Galina, Mai, Phuong L., Mannermaa, Arto, Margolin, Sara, Mariette, Frederique, Marme, Frederik, M. Martens, John W., G. Massuger, Leon F.A., Maugard, Christine, Mazoyer, Sylvie, McGuffog, Lesley, McGuire, Valerie, McLean, Catriona, McNeish, Iain, Meindl, Alfons, Menegaux, Florence, Menéndez, Primitiva, Menkiszak, Janusz, Menon, Usha, Mensenkamp, Arjen R., Miller, Nicola, Milne, Roger L., Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Müller, Heiko, Mulligan, Anna Marie, Muranen, Taru A., Narod, Steven A., Nathanson, Katherine L., Ness, Roberta B., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Nielsen, Finn C., Nielsen, Sune F., Nordestgaard, Børge G., Nussbaum, Robert L., Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olson, Sara H., Oosterwijk, Jan C., Orlow, Irene, Orr, Nick, Orsulic, Sandra, Osorio, Ana, Ottini, Laura, Paul, James, Pearce, Celeste L., Sokilde Pedersen, Inge, Peissel, Bernard, Pejovic, Tanja, Pelttari, Liisa M., Perkins, Jo, Permuth-Wey, Jenny, Peterlongo, Paolo, Peto, Julian, Phelan, Catherine M., Phillips, Kelly-Anne, Piedmonte, Marion, Pike, Malcolm C., Platte, Radka, Plisiecka-Halasa, Joanna, Poole, Elizabeth M., Poppe, Bruce, Pylkäs, Katri, Radice, Paolo, Ramus, Susan J., Rebbeck, Timothy R., R. Reed, Malcolm W., Rennert, Gad, Risch, Harvey A., Robson, Mark, Rodriguez, Gustavo C., Romero, Atocha, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo, Salani, Ritu, Salvesen, Helga B., Sawyer, Elinor J., Schildkraut, Joellen M., Schmidt, Marjanka K., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schrauder, Michael G., Schumacher, Fredrick, Schwaab, Ira, Scuvera, Giulietta, Sellers, Thomas A., Severi, Gianluca, Seynaeve, Caroline M., Shah, Mitul, Shrubsole, Martha, Siddiqui, Nadeem, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sinilnikova, Olga M., Smeets, Dominiek, Sohn, Christof, Soller, Maria, Song, Honglin, Soucy, Penny, Southey, Melissa C., Stegmaier, Christa, Stoppa-Lyonnet, Dominique, Sucheston, Lara, SWE-BRCA, Swerdlow, Anthony, Tangen, Ingvild L., Tea, Muy-Kheng, Teixeira, Manuel R., Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Thompson, Pamela J., Tihomirova, Laima, Tischkowitz, Marc, Ewart Toland, Amanda, M. Tollenaar, Rob A.E., Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Tsimiklis, Helen, Tung, Nadine, Tworoger, Shelley S., Tyrer, Jonathan P., Vachon, Celine M., Van 't Veer, Laura J., van Altena, Anne M., Van Asperen, C.J., van den Berg, David, van den Ouweland, Ans M.W., van Doorn, Helena C., Van Nieuwenhuysen, Els, van Rensburg, Elizabeth J., Vergote, Ignace, Verhoef, Senno, Vierkant, Robert A., Vijai, Joseph, Vitonis, Allison F., von Wachenfeldt, Anna, Walsh, Christine, Wang, Qin, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weischer, Maren, Weitzel, Jeffrey N., Weltens, Caroline, Wentzensen, Nicolas, Whittemore, Alice S., Wilkens, Lynne R., Winqvist, Robert, Wu, Anna H., Wu, Xifeng, Yang, Hannah P., Zaffaroni, Daniela, Zamora, M. Pilar, Zheng, Wei, Ziogas, Argyrios, Chenevix-Trench, Georgia, P. Pharoah, Paul D., Rookus, Matti A., Hooning, Maartje J., and Goode, Ellen L.

45. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author

Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, BOCS, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, JY, Park, SK, Yoo, KY, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guénel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, González-Neira, A, Benitez, J, Zamora, MP, Perez, JI, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MW, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, ConFab Investigators, AOCS Group, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NA, Tan, GH, Hooning, MJ, Hollestelle, A, Martens, JW, Collée, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, CY, Hsiung, CN, Wu, PE, Hou, MF, Kristensen, VN, Nord, S, Alnaes, GI, NBCS, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, KT, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, JM, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Brüning, T, GENICA Network, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Dörk, T, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Devilee, P, Tollenaar, RA, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Alonso, MR, Álvarez, N, Herrero, D, Simard, J, Pharoah, PP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, Easton, DF, Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, BOCS, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, JY, Park, SK, Yoo, KY, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guénel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, González-Neira, A, Benitez, J, Zamora, MP, Perez, JI, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MW, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, ConFab Investigators, AOCS Group, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NA, Tan, GH, Hooning, MJ, Hollestelle, A, Martens, JW, Collée, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, CY, Hsiung, CN, Wu, PE, Hou, MF, Kristensen, VN, Nord, S, Alnaes, GI, NBCS, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, KT, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, JM, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labrèche, F, Dumont, M, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Brüning, T, GENICA Network, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Dörk, T, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Devilee, P, Tollenaar, RA, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Alonso, MR, Álvarez, N, Herrero, D, Simard, J, Pharoah, PP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, and Easton, DF

46. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author

Jing Hua Zhao, Vilmundur Gudnason, Robin Haring, Enda M. Byrne, Christian Gieger, Marek Zygmunt, Lude Franke, Peter Kraft, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Thorkild I. A. Sørensen, Aida Karina Dieffenbach, André G. Uitterlinden, Grant W. Montgomery, Graham G. Giles, Felix R. Day, Anja Rudolph, Arto Mannermaa, Sven Bergmann, Nora Franceschini, Julian Peto, Ellen W. Demerath, Diana L. Cousminer, Wei Ang, Gudmar Thorleifsson, Patrick F. McArdle, Dieter Flesch-Janys, Albertine J. Oldehinkel, Irene L. Andrulis, Aarno Palotie, Nicholas J. Timpson, Paolo Peterlongo, Johan G. Eriksson, Bernardo Bonanni, Dorret I. Boomsma, J. Margriet Collée, Immaculata De Vivo, Bjarke Feenstra, Teresa Ferreira, Cornelia M. van Duijn, Nancy L. Pedersen, Deborah J. Thompson, Peter Vollenweider, Douglas F. Easton, Pascal Guénel, Anna Maria Storniolo, Erik Ingelsson, Gisli Masson, Annika Lindblom, Stefania Bandinelli, Elisabeth Widen, Doris Stöckl, Veikko Salomaa, Zoltán Kutalik, Nicholas J. Wareham, Joanne M. Murabito, Eleonora Porcu, Fergus J. Couch, Katri Pylkäs, Luigi Ferrucci, Wendy L. McArdle, Frank Geller, Andrea D. Coviello, Lynda M. Rose, Daniel L. Koller, Ute Hamann, Ulla Sovio, Daniel F. Gudbjartsson, Georgia Chenevix-Trench, Roger L. Milne, Unnur Thorsteinsdottir, Paul M. Ridker, Henry Völzke, John R. B. Perry, Stephen J. Chanock, Tanguy Corre, Mads Melbye, Ben A. Oostra, Albert V. Smith, Tõnu Esko, Melissa E. Garcia, Debbie A Lawlor, Meir J. Stampfer, Per Hall, Patrick Sulem, Massimo Mangino, Nicholas G. Martin, David J. Hunter, Laura Crisponi, Tatiana Foroud, Antonietta Robino, Michael J. Econs, Susan M. Ring, Natalia Tšernikova, Dirkje S. Postma, Lavinia Paternoster, Peter A. Fasching, Tamara B. Harris, Ellen A. Nohr, Javier Benitez, Ruth J. F. Loos, Robert Winqvist, Andres Metspalu, Jenny A. Visser, Heather A. Boyd, Jonathan Tyrer, Alexander Teumer, Tim D. Spector, Sandra Lai, Douglas P. Kiel, Kamila Czene, Hiltrud Brauch, George Davey Smith, Julia A. Knight, Erin K. Wagner, Suiqun Guo, Tune H. Pers, Patrik K. E. Magnusson, Kathryn L. Lunetta, Hoda Anton-Culver, Marjanka K. Schmidt, George McMahon, Ken K. Ong, Adamo Pio D'Adamo, Veli-Matti Kosma, Jinhui Chen, Paul D.P. Pharoah, Diether Lambrechts, Femke Atsma, Serena Sanna, Ilja M. Nolte, Eco de Geus, Daniel I. Chasman, Emmi Tikkanen, John L. Hopper, Anna Murray, Laura M. Yerges-Armstrong, Sanela Kjellqvist, Eva Albrecht, Hermann Brenner, Paolo Gasparini, Bruce H. R. Wolffenbuttel, Alison M. Dunning, John P. Rice, Craig E. Pennell, Mark I. McCarthy, Andrea Ganna, Henri Wallaschofski, Frank B. Hu, Gérard Waeber, Henrik Flyger, Evelin Mihailov, Peter Devilee, Lisette Stolk, Behrooz Z. Alizadeh, Jouke-Jan Hottenga, Najaf Amin, Patrick Neven, Reedik Mägi, Kyriaki Michailidou, Kari Stefansson, Munro Peacock, Julie E. Buring, Laura J. Bierut, Cathy E. Elks, Marjo-Riitta Järvelin, Montserrat Garcia-Closas, Anneli Pouta, David Schlessinger, Harold Snieder, Chunyan He, Joe Dennis, Heli Nevanlinna, Gonneke Willemsen, Andrew C. Heath, Elizabeth A. Streeten, Albert Hofman, Angela Cox, Maartje J. Hooning, Lili Milani, Margaret J. Wright, Fernando Rivadeneira, Gudny Eiriksdottir, Mellissa C. Southey, Qin Wang, Paolo Radice, Manjeet K. Bolla, Kay-Tee Khaw, Carl Blomqvist, Melanie Waldenberger, Sheila Ulivi, David Couper, Jenny Chang-Claude, David Karasik, Stig E. Bojesen, Andrew D. Johnson, David P. Strachan, Perry, John [0000-0001-6483-3771], Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Zhao, Jing Hua [0000-0003-4930-3582], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], Khaw, Kay-Tee [0000-0002-8802-2903], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Australian Ovarian Cancer Study, GENICA Network, kConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, Cousminer, D.L., Stergiakouli, E., Berry, D.J., Ang, W., Groen-Blokhuis, M.M., Körner, A., Siitonen, N., Ntalla, I., Marinelli, M., Perry, J.R., Kettunen, J., Jansen, R., Surakka, I., Timpson, N.J., Ring, S., McMahon, G., Power, C., Wang, C., Kähönen, M., Viikari, J., Lehtimäki, T., Middeldorp, C.M., Hulshoff Pol, H.E., Neef, M., Weise, S., Pahkala, K., Niinikoski, H., Zeggini, E., Panoutsopoulou, K., Bustamante, M., Penninx, B.W., Murabito, J., Torrent, M., Dedoussis, G.V., Kiess, W., Boomsma, D.I., Pennell, C.E., Raitakari, O.T., Hyppönen, E., Davey Smith, G., Ripatti, S., McCarthy, M.I., Widén, E., Alizadeh, B.Z., de Boer, R.A., Boezen, H.M., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, H.L., van der Klauw, M.M., Navis, G., Ormel, J., Postma, D., Rosmalen, J.G., Slaets, J.P., Snieder, H., Stolk, R.P., Wolffenbuttel, B.H., Wijmenga, C., Forouhi, N., Kerrison, N.D., Langenberg, C., Scott, R.A., Sharp, S.J., Sims, M., Barroso, I., Deloukas, P., Arriola, L., Balkau, B., Barricarte, A., Boeing, H., Franks, P.W., Gonzalez, C., Grioni, S., Kaaks, R., Key, T.J., Navarro, C., Nilsson, P.M., Overvad, K., Palli, D., Panico, S., Quirós, J., Rolandsson, O., Sacerdote, C., Sánchez, M.J., Slimani, N., Tjonneland, A., Tumino, R., van der A, D.L., van der Schouw, Y.T., Riboli, E., Wareham, N.J., Bowtell, D.D., Green, A., Chenevix-Trench, G., deFazio, A., Gertig, D., Webb, P.M., Brauch, H., Justenhoven, C., Hamann, U., Ko, Y.D., Baisch, C., Fischer, H.P., Pesch, B., Rabstein, S., Spickenheuer, A., Harth, V., Aghmesheh, M., Amor, D., Andrews, L., Antill, Y., Armitage, S., Arnold, L., Balleine, R., Bankier, A., Bastick, P., Beesley, J., Beilby, J., Bennett, I., Bennett, B., Berry, G., Blackburn, A., Bogwitz, M., Brennan, M., Brown, M., Buckley, M., Burgess, M., Burke, J., Butow, P., Byron, K., Callen, D., Campbell, I., Chauhan, D., Christian, A., Clarke, C., Colley, A., Cotton, D., Crook, A., Cui, J., Culling, B., Cummings, M., Dawson, S.J., Delatycki, M., Dickson, R., Dixon, J., Dobrovic, A., Dudding, T., Edkins, T., Edwards, S., Eisenbruch, M., Farshid, G., Fawcett, S., Fellows, A., Fenton, G., Field, M., Firgaira, F., Flanagan, J., Fleming, J., Fong, P., Forbes, J., Fox, S., French, J., Friedlander, M., Gaff, C., Gardner, M., Gattas, M., George, P., Giles, G., Gill, G., Goldblatt, J., Greening, S., Grist, S., Eric, H., Hardie, K., Harris, M., Hart, S., Hayward, N., Healey, S., Heiniger, L., Hopper, J., Humphrey, E., Hunt, C., James, P., Jenkins, M., Jones, A., Kefford, R., Kidd, A., Kiely, B., Kirk, J., Koehler, J., Kollias, J., Kovalenko, S., Lakhani, S., Leaming, A., Leary, J., Lim, J., Lindeman, G., Lipton, L., Lobb, L., Mann, G., Marsh, D., McLachlan, S.A., Meiser, B., Meldrum, C., Milne, R., Mitchell, G., Newman, B., O'Connell, S., O'Loughlin, I., Osborne, R., Pachter, N., Patterson, B., Peters, L., Phillips, K., Price, M., Purser, L., Reeve, J., Reeve, T., Richards, R., Rickard, E., Robinson, B., Rudzki, B., Saleh, M., Salisbury, E., Sambrook, J., Saunders, C., Saunus, J., Sayer, R., Scott, E., Scott, R., Scott, C., Seshadri, R., Sexton, A., Sharma, R., Shelling, A., Simpson, P., Southey, M., Spurdle, A., Suthers, G., Sykes, P., Taylor, D., Taylor, J., Thierry, B., Thompson, E., Thorne, H., Townshend, S., Trainer, A., Tran, L., Tucker, K., Tyler, J., Visvader, J., Walker, L., Walpole, I., Waring, P., Warner, B., Warren, G., Williams, R., Wilson, J., Winship, I., Wu, K., Young, M.A., Public Health, Internal Medicine, Epidemiology, Clinical Genetics, Medical Oncology, Child and Adolescent Psychiatry / Psychology, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Research Institute for Asthma and COPD (GRIAC), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Political Science, Perry, John R. B, Day, Felix, Elks, Cathy E, Sulem, Patrick, Thompson, Deborah J, Ferreira, Teresa, He, Chunyan, Chasman, Daniel I, Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q, Corre, Tanguy, Cousminer, Diana L, Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D, Kjellqvist, Sanela, Lunetta, Kathryn L, Mcmahon, George, Nolte, Ilja M, Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K, Amin, Najaf, Bierut, Laura J, Byrne, Enda M, Hottenga, Jouke Jan, Koller, Daniel L, Mangino, Massimo, Pers, Tune H, Yerges Armstrong, Laura M, Hua Zhao, Jing, Andrulis, Irene L, Anton Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E, Chang Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix Trench, Georgia, Collée, J. Margriet, Couch, Fergus J, Couper, David, Coviello, Andrea D, Cox, Angela, Czene, Kamila, D'Adamo, Adamo Pio, Davey Smith, George, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K, Dunning, Alison M, Eiriksdottir, Gudny, Eriksson, Johan G, Fasching, Peter A, Ferrucci, Luigi, Flesch Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E, García Closas, Montserrat, Geller, Frank, de Geus, Eco E. J, Giles, Graham G, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A, Heath, Andrew C, Hofman, Albert, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Hunter, David J, Karasik, David, Kiel, Douglas P, Knight, Julia A, Kosma, Veli Matti, Kutalik, Zoltan, Lai, Sandra, Lambrechts, Diether, Lindblom, Annika, Mägi, Reedik, Magnusson, Patrik K, Mannermaa, Arto, Martin, Nicholas G, Masson, Gisli, Mcardle, Patrick F, Mcardle, Wendy L, Melbye, Mad, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L, Nevanlinna, Heli, Neven, Patrick, Nohr, Ellen A, Oldehinkel, Albertine J, Oostra, Ben A, Palotie, Aarno, Peacock, Munro, Pedersen, Nancy L, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P, Postma, Dirkje S, Pouta, Anneli, Pylkäs, Katri, Radice, Paolo, Ring, Susan, Rivadeneira, Fernando, Robino, Antonietta, Rose, Lynda M, Rudolph, Anja, Salomaa, Veikko, Sanna, Serena, Schlessinger, David, Schmidt, Marjanka K, Southey, Mellissa C, Sovio, Ulla, Stampfer, Meir J, Stöckl, Dori, Storniolo, Anna M, Timpson, Nicholas J, Tyrer, Jonathan, Visser, Jenny A, Vollenweider, Peter, Völzke, Henry, Waeber, Gerard, Waldenberger, Melanie, Wallaschofski, Henri, Wang, Qin, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R, Wright, Margaret J, Boomsma, Dorret I, Econs, Michael J, Khaw, Kay Tee, Loos, Ruth J. F, Mccarthy, Mark I, Montgomery, Grant W, Rice, John P, Streeten, Elizabeth A, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Alizadeh, Behrooz Z, Bergmann, Sven, Boerwinkle, Eric, Boyd, Heather A, Crisponi, Laura, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B, Ingelsson, Erik, Järvelin, Marjo Riitta, Kraft, Peter, Lawlor, Debbie, Metspalu, Andre, Pennell, Craig E, Ridker, Paul M, Snieder, Harold, Sørensen, Thorkild I. A, Spector, Tim D, Strachan, David P, Uitterlinden, André G, Wareham, Nicholas J, Widen, Elisabeth, Zygmunt, Marek, Murray, Anna, Easton, Douglas F, Stefansson, Kari, Murabito, Joanne M, Ong, Ken K., Panico, Salvatore, Perry, John R. B., Elks, Cathy E., Thompson, Deborah J., Chasman, Daniel I., Ang, Wei Q., Cousminer, Diana L., Johnson, Andrew D., Lunetta, Kathryn L., Nolte, Ilja M., Smith, Albert V., Wagner, Erin K., Bierut, Laura J., Byrne, Enda M., Koller, Daniel L., Pers, Tune H., Yerges Armstrong, Laura M., Zhao, Jing Hua, Andrulis, Irene L., Beckmann, Matthias W., Bojesen, Stig E., Bolla, Manjeet K., Buring, Julie E., Couch, Fergus J., Coviello, Andrea D., D'Adamo, ADAMO PIO, Smith, George Davey, Demerath, Ellen W., Dieffenbach, Aida K., Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., Garcia, Melissa E., De Geus, Eco E. J., Giles, Graham G., Gudbjartsson, Daniel F., Hartman, Catharina A., Heath, Andrew C., Hooning, Maartje J., Hopper, John L., Hu, Frank B., Hunter, David J., Kiel, Douglas P., Knight, Julia A., Magnusson, Patrik K., Martin, Nicholas G., Mcardle, Patrick F., Mcardle, Wendy L., Milne, Roger L., Nohr, Ellen A., Oldehinkel, Albertine J., Oostra, Ben A., Pedersen, Nancy L., Pharoah, Paul D. P., Postma, Dirkje S., Rose, Lynda M., Schmidt, Marjanka K., Southey, Mellissa C., Stampfer, Meir J., Storniolo, Anna M., Timpson, Nicholas J., Visser, Jenny A., Wolffenbuttel, Bruce H. R., Wright, Margaret J., Boomsma, Dorret I., Econs, Michael J., Loos, Ruth J. F., Mccarthy, Mark I., Montgomery, Grant W., Rice, John P., Streeten, Elizabeth A., Van Duijn, Cornelia M., Alizadeh, Behrooz Z., Boyd, Heather A., Harris, Tamara B., Pennell, Craig E., Ridker, Paul M., Sørensen, Thorkild I. A., Spector, Tim D., Strachan, David P., Uitterlinden, André G., Wareham, Nicholas J., Easton, Douglas F., and Murabito, Joanne M.

Subjects
Netherlands Twin Register (NTR), Male, Parents, CENTRAL PRECOCIOUS PUBERTY, Genome-wide association study, Disease, VARIANTS, DISEASE, Body Mass Index, 0302 clinical medicine, Adolescent, Age Factors, Alleles, Breast Neoplasms/genetics, Cardiovascular Diseases/genetics, Child, Diabetes Mellitus, Type 2/genetics, Europe/ethnology, Female, Genetic Loci/genetics, Genome-Wide Association Study, Genomic Imprinting/genetics, Humans, Hypothalamo-Hypophyseal System/physiology, Intercellular Signaling Peptides and Proteins/genetics, Membrane Proteins/genetics, Menarche/genetics, Obesity/genetics, Ovary/physiology, Polymorphism, Single Nucleotide/genetics, Potassium Channels, Tandem Pore Domain/genetics, Proteins/genetics, Quantitative Trait Loci/genetics, Receptors, GABA-B/metabolism, Receptors, Retinoic Acid/metabolism, Ribonucleoproteins/genetics, Intercellular Signaling Peptides and Protein, Age Factor, Tandem Pore Domain, GENE-EXPRESSION, 0303 health sciences, BREAST-CANCER RISK, 3. Good health, Ribonucleoproteins, Cardiovascular Diseases, Menarche, Intercellular Signaling Peptides and Proteins, Science & Technology - Other Topics, GENICA Network, Breast Neoplasm, Type 2, Human, Hypothalamo-Hypophyseal System, Quantitative Trait Loci, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, REVEALS, Diabetes Mellitus, Polymorphism, METAANALYSIS, Science & Technology, ta1184, Calcium-Binding Proteins, Proteins, HUMAN PREFRONTAL CORTEX, ta3121, ta3123, Diabetes Mellitus, Type 2, Genetic Loci, CELLS, 030217 neurology & neurosurgery, LifeLines Cohort Study, Potassium Channels, Receptors, Retinoic Acid, Retinoic Acid, Australian Ovarian Cancer Study, Polymorphism (computer science), Cardiovascular Disease, Receptors, WIDE ASSOCIATION, Membrane Protein, Allele, 2. Zero hunger, Genetics, Multidisciplinary, Single Nucleotide, Europe, Multidisciplinary Sciences, kConFab, Breast Neoplasms, Genomic Imprinting, Membrane Proteins, Obesity, Ovary, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Receptors, GABA-B, General Science & Technology, Ubiquitin-Protein Ligases, Quantitative trait locus, Biology, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Early Growth Genetics (EGG) Consortium, 030304 developmental biology, Protein, GABA-B, Ribonucleoprotein, InterAct Consortium, Genetic architecture, Parent, Genomic imprinting
Abstract

Contains fulltext : 136472.pdf (Publisher’s version ) (Closed access) Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

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