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1. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou

Subjects
Science
Abstract

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Published
2021
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2. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou

Subjects
Science
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4

Published
2021
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3. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

Author

Hisani N Horne, Charles C Chung, Han Zhang, Kai Yu, Ludmila Prokunina-Olsson, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Joe Dennis, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Kenneth Muir, Artitaya Lophatananon, Peter A Fasching, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Elinor J Sawyer, Ian Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, Hoda Anton-Culver, Susan L Neuhausen, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Heli Nevanlinna, Sofia Khan, Keitaro Matsuo, Hiroji Iwata, Thilo Dörk, Natalia V Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Georgia Chenevix-Trench, kConFab/AOCS Investigators, Anna H Wu, David Ven den Berg, Ann Smeets, Hui Zhao, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Monica Barile, Fergus J Couch, Celine Vachon, Graham G Giles, Roger L Milne, Christopher A Haiman, Loic Le Marchand, Mark S Goldberg, Soo H Teo, Nur A M Taib, Vessela Kristensen, Anne-Lise Borresen-Dale, Wei Zheng, Martha Shrubsole, Robert Winqvist, Arja Jukkola-Vuorinen, Irene L Andrulis, Julia A Knight, Peter Devilee, Caroline Seynaeve, Montserrat García-Closas, Kamila Czene, Hatef Darabi, Antoinette Hollestelle, John W M Martens, Jingmei Li, Wei Lu, Xiao-Ou Shu, Angela Cox, Simon S Cross, William Blot, Qiuyin Cai, Mitul Shah, Craig Luccarini, Caroline Baynes, Patricia Harrington, Daehee Kang, Ji-Yeob Choi, Mikael Hartman, Kee Seng Chia, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubinski, Suleeporn Sangrajrang, Paul Brennan, Susan Slager, Drakoulis Yannoukakos, Chen-Yang Shen, Ming-Feng Hou, Anthony Swerdlow, Nick Orr, Jacques Simard, Per Hall, Paul D P Pharoah, Douglas F Easton, Stephen J Chanock, Alison M Dunning, and Jonine D Figueroa

Subjects
Medicine, Science
Abstract

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

Published
2016
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4. Functional polymorphisms in the TERT promoter are associated with risk of serous epithelial ovarian and breast cancers.

Author

Jonathan Beesley, Hilda A Pickett, Sharon E Johnatty, Alison M Dunning, Xiaoqing Chen, Jun Li, Kyriaki Michailidou, Yi Lu, David N Rider, Rachel T Palmieri, Michael D Stutz, Diether Lambrechts, Evelyn Despierre, Sandrina Lambrechts, Ignace Vergote, Jenny Chang-Claude, Stefan Nickels, Alina Vrieling, Dieter Flesch-Janys, Shan Wang-Gohrke, Ursula Eilber, Natalia Bogdanova, Natalia Antonenkova, Ingo B Runnebaum, Thilo Dörk, Marc T Goodman, Galina Lurie, Lynne R Wilkens, Rayna K Matsuno, Lambertus A Kiemeney, Katja K H Aben, Tamara Marees, Leon F A G Massuger, Brooke L Fridley, Robert A Vierkant, Elisa V Bandera, Sara H Olson, Irene Orlow, Lorna Rodriguez-Rodriguez, Linda S Cook, Nhu D Le, Angela Brooks-Wilson, Linda E Kelemen, Ian Campbell, Simon A Gayther, Susan J Ramus, Aleksandra Gentry-Maharaj, Usha Menon, Shahana Ahmed, Caroline Baynes, Paul D Pharoah, kConFab Investigators, Australian Ovarian Cancer Study Group, ABCTB Investigators, Kenneth Muir, Artitaya Lophatananon, Arkom Chaiwerawattana, Surapon Wiangnon, Stuart Macgregor, Douglas F Easton, Roger R Reddel, Ellen L Goode, Georgia Chenevix-Trench, and Ovarian Cancer Association Consortium

Subjects
Medicine, Science
Abstract

Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.

Published
2011
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5. Supplementary Tables 1 and 2; legend for Supplementary Table 3 from TGF-β Signaling Pathway and Breast Cancer Susceptibility

Author

Alison M. Dunning, James C. Metcalfe, Robin Hesketh, Douglas F. Easton, Paul D. Pharoah, Jolanta Lissowska, Jonine Figueroa, Montserrat Garcia-Closas, Manjeet K. Humphreys, Kristy Driver, Caroline Baynes, Craig Luccarini, and Serena Scollen

Abstract

Supplementary Tables 1 and 2; legend for Supplementary Table 3 from TGF-β Signaling Pathway and Breast Cancer Susceptibility

Published
2023
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7. Data from TGF-β Signaling Pathway and Breast Cancer Susceptibility

Author

Alison M. Dunning, James C. Metcalfe, Robin Hesketh, Douglas F. Easton, Paul D. Pharoah, Jolanta Lissowska, Jonine Figueroa, Montserrat Garcia-Closas, Manjeet K. Humphreys, Kristy Driver, Caroline Baynes, Craig Luccarini, and Serena Scollen

Abstract

Background: TGF-β acts as a suppressor of primary tumor initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for single-nucleotide polymorphisms (SNP) tagging 17 genes in the canonical TGF-β ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signaling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, and SMAD7 [Approved Human Gene Nomenclature Committee gene names: ACVRL1 (for ALK1) and ENG (for Endoglin)].Methods: Three-hundred-fifty-four tag SNPs (minor allele frequency > 0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study. Significant associations were meta-analyzed with data from the NCI Polish Breast Cancer Study (PBCS; 1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC).Results: Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263), and TGFBR2 (rs4522809), were detected in SEARCH; however, associations became weaker in meta-analyses including data from PBCS and BCAC. Tumor subtype analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR−) tumors [1.18 (95% CI: 1.09–1.28), 4.1 × 10−5 (P value for heterogeneity of ORs by PR status = 2.3 × 10−4)]. There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilizing ALK1/SMADs 1&5 that promotes angiogenesis.Conclusion: Common variation in the TGF-β ALK5/SMADs 2&3 signaling pathway, which initiates signaling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumor subtypes.Impact: The subtype specific associations require very large studies to be confirmed. Cancer Epidemiol Biomarkers Prev; 20(6); 1112–9. ©2011 AACR.

Published
2023
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8. Breast Cancer Risk in Women from Ghana Carrying Rare Germline Pathogenic Mutations

Author

Thomas U. Ahearn, Parichoy Pal Choudhury, Andriy Derkach, Beatrice Wiafe-Addai, Baffour Awuah, Joel Yarney, Lawrence Edusei, Nicholas Titiloye, Ernest Adjei, Verna Vanderpuye, Francis Aitpillah, Florence Dedey, Joseph Oppong, Ernest Baawuah Osei-Bonsu, Máire A. Duggan, Louise A. Brinton, Jamie Allen, Craig Luccarini, Caroline Baynes, Sara Carvalho, Alison M. Dunning, Brittny C. Davis Lynn, Stephen J. Chanock, Belynda D. Hicks, Meredith Yeager, Nilanjan Chatterjee, Richard Biritwum, Joe Nat Clegg-Lamptey, Kofi Nyarko, Seth Wiafe, Daniel Ansong, Douglas F. Easton, Jonine D. Figueroa, Montserrat Garcia-Closas, Ahearn, Thomas U [0000-0003-0771-7752], Derkach, Andriy [0000-0003-2178-8493], Titiloye, Nicholas [0000-0001-7578-5859], Adjei, Ernest [0000-0002-4004-3334], Aitpillah, Francis [0000-0001-9495-6887], Dedey, Florence [0000-0001-6806-9256], Oppong, Joseph [0000-0003-2455-2734], Osei-Bonsu, Ernest Baawuah [0000-0002-3657-3519], Duggan, Máire A [0000-0001-6625-7683], Brinton, Louise A [0000-0003-3853-8562], Allen, Jamie [0000-0002-8677-2225], Carvalho, Sara [0000-0002-5512-4540], Dunning, Alison M [0000-0001-6651-7166], Chanock, Stephen J [0000-0002-2324-3393], Hicks, Belynda D [0000-0001-8014-4888], Biritwum, Richard [0000-0002-0025-7354], Clegg-Lamptey, Joe Nat [0000-0003-0497-071X], Wiafe, Seth [0000-0001-6085-9405], Ansong, Daniel [0000-0003-1328-9117], Garcia-Closas, Montserrat [0000-0003-1033-2650], and Apollo - University of Cambridge Repository

Subjects
Risk, Breast cancer, Oncology, Epidemiology, pathogenic germline variants, population-based case-control study, Humans, absolute risk, Breast Neoplasms, Female, Genetic Predisposition to Disease, Ghana, Germ-Line Mutation
Abstract

Background: Risk estimates for women carrying germline mutations in breast cancer susceptibility genes are mainly based on studies of European ancestry women. Methods: We investigated associations between pathogenic variants (PV) in 34 genes with breast cancer risk in 871 cases [307 estrogen receptor (ER)-positive, 321 ER-negative, and 243 ER-unknown] and 1,563 controls in the Ghana Breast Health Study (GBHS), and estimated lifetime risk for carriers. We compared results with those for European, Asian, and African American ancestry women. Results: The frequency of PV in GBHS for nine breast cancer genes was 8.38% in cases and 1.22% in controls. Relative risk estimates for overall breast cancer were: (OR, 13.70; 95% confidence interval (CI), 4.03–46.51) for BRCA1, (OR, 7.02; 95% CI, 3.17–15.54) for BRCA2, (OR, 17.25; 95% CI, 2.15–138.13) for PALB2, 5 cases and no controls carried TP53 PVs, and 2.10, (0.72–6.14) for moderate-risk genes combined (ATM, BARD1, CHEK2, RAD51C, RAD52D). These estimates were similar to those previously reported in other populations and were modified by ER status. No other genes evaluated had mutations associated at P < 0.05 with overall risk. The estimated lifetime risks for mutation carriers in BRCA1, BRCA2, and PALB2 and moderate-risk genes were 18.4%, 9.8%, 22.4%, and 3.1%, respectively, markedly lower than in Western populations with higher baseline risks. Conclusions: We confirmed associations between PV and breast cancer risk in Ghanaian women and provide absolute risk estimates that could inform counseling in Ghana and other West African countries. Impact: These findings have direct relevance for breast cancer genetic counseling for women in West Africa.

Published
2022
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9. Targeted Resequencing of the Coding Sequence of 38 Genes Near Breast Cancer GWAS Loci in a Large Case–Control Study

Author

Douglas F. Easton, Alison M. Dunning, Craig Luccarini, Qin Wang, Caroline Baynes, Karen A. Pooley, Don M. Conroy, Paul D.P. Pharoah, Robert Luben, Jamie Allen, Mitul Shah, Judith E. Brown, Brennan Decker, Manjeet K. Bolla, Shahana Ahmed, and Elaine A. Ostrander

Subjects
0301 basic medicine, Linkage disequilibrium, Epidemiology, Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Biology, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Gene Frequency, medicine, Humans, Genetic Predisposition to Disease, Allele, Gene, Genetic association, Genetics, Case-control study, medicine.disease, 030104 developmental biology, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Female, Genome-Wide Association Study
Abstract

Background: Genes regulated by breast cancer risk alleles identified through genome-wide association studies (GWAS) may harbor rare coding risk alleles. Methods: We sequenced the coding regions for 38 genes within 500 kb of 38 lead GWAS SNPs in 13,538 breast cancer cases and 5,518 controls. Results: Truncating variants in these genes were rare, and were not associated with breast cancer risk. Burden testing of rare missense variants highlighted 5 genes with some suggestion of an association with breast cancer, although none met the multiple testing thresholds: MKL1, FTO, NEK10, MDM4, and COX11. Six common alleles in COX11, MAP3K1 (two), and NEK10 (three) were associated at the P < 0.0001 significance level, but these likely reflect linkage disequilibrium with causal regulatory variants. Conclusions: There was no evidence that rare coding variants in these genes confer substantial breast cancer risks. However, more modest effect sizes could not be ruled out. Impact: We tested the hypothesis that rare variants in 38 genes near breast cancer GWAS loci may mediate risk. These variants do not appear to play a major role in breast cancer heritability.

Published
2019
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10. Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Author

Joanna Lim, Rick A. C. M. Boonen, Milan Sharma, Ern Yu Tan, Craig Luccarini, Su-Ming Tan, Jingmei Li, Douglas F. Easton, Sabine Knaup, Benita Kiat Tee Tan, Soo Hwang Teo, Weang Kee Ho, Alison M. Dunning, Chan Eng Chong, Shivaani Mariapun, Kartini Rahmat, Sara Carvalho, Rob M. van Dam, Mee Hoong See, Eldarina Wijaya, Pei Sze Ng, Caroline Baynes, Swee Ho Lim, Antonis C. Antoniou, Sook-Yee Yoon, Haico van Attikum, Mikael Hartman, Cheng Har Yip, Nur Aishah Taib, Veronique Kiat-Mien Tan, Ng, Pei Sze [0000-0001-5403-2065], Yoon, Sook-Yee [0000-0002-9992-0901], Teo, Soo Hwang [0000-0002-0444-590X], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, PALB2, Population, Breast Neoplasms, Biology, Germline, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Germline mutation, Genetics, medicine, Animals, Humans, Missense mutation, education, Cancer genetics, Genetics (clinical), genetic predisposition to disease, Singapore, education.field_of_study, Malaysia, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Relative risk, Mutation testing, Female, Fanconi Anemia Complementation Group N Protein, germ-line mutation
Abstract

BackgroundRare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.MethodsMutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.ResultsPTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, pPALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.ConclusionDespite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

Published
2021
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11. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Pascal Guénel, John J. Spinelli, Hoda Anton-Culver, Veli-Matti Kosma, Beth Y. Karlan, Antonis C. Antoniou, Brian D. Carter, Drakoulis Yannoukakos, Orland Diez, Montserrat Garcia-Closas, Uffe Birk Jensen, Susan M. Gapstur, Christine L. Clarke, Florentia Fostira, Trinidad Caldés, Wei Zheng, Diana Eccles, Don M. Conroy, Kristan J. Aronson, Sara Margolin, Thomas U. Ahearn, Hedy S. Rennert, Evgeny N. Imyanitov, Rulla M. Tamimi, Mary Beth Terry, Jenny Chang-Claude, Per Hall, Daniel R. Barnes, Alex Teulé, D. Gareth Evans, Åke Borg, Frans B. L. Hogervorst, Yon-Dschun Ko, Celine M. Vachon, Graham G. Giles, Simona Agata, Gad Rennert, Yuan Chun Ding, J. Margriet Collée, Alison M. Dunning, Regina M. Santella, Banu Arun, William J. Tapper, Melissa C. Southey, Finn Cilius Nielsen, Michael T. Parsons, Marjanka K. Schmidt, Alfons Meindl, Vassilios Georgoulias, Simon A. Gayther, Debra Frost, Noura Mebirouk, Hebon Investigators, Austin Miller, Sue K. Park, Anthony J Swerdlow, Emmanouil Saloustros, Isabel dos-Santos-Silva, Laura Ottini, Jack A. Taylor, Siranoush Manoukian, Maria A. Caligo, Douglas F. Easton, Christoph Engel, Antoinette Hollestelle, Ana Vega, Muriel A. Adank, Mia M. Gaudet, Heko Becher, Lothar Haeberle, Priyanka Sharma, Katherine L. Nathanson, Mads Thomassen, Miriam Dwek, Manuela Gago-Dominguez, Hiltrud Brauch, Kamila Czene, Peter A. Fasching, Peter J. Hulick, David E. Goldgar, Lesley McGuffog, Anna Jakubowska, Paul D.P. Pharoah, Adrià López-Fernández, Bruce Poppe, Volker Arndt, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Jennifer Stone, Wendy K. Chung, Joseph Vijai, Qin Wang, Penny Soucy, Miquel Angel Pujana, Diether Lambrechts, Vanesa García-Barberán, Andrea Gehrig, Anna González-Neira, Thérèse Truong, Jenny Lester, Wei He, Dale P. Sandler, Rita K. Schmutzler, Julian Peto, A. Heather Eliassen, Paolo Radice, Yael Laitman, Johanna Rantala, Kelly-Anne Phillips, Amanda E. Toland, Bernardo Bonanni, Muhammad Usman Rashid, Heli Nevanlinna, John L. Hopper, Kevin Punie, kConFab Investigators, Thilo Dörk, Judy Garber, Alison H. Trainer, Irene L. Andrulis, Jeffrey N. Weitzel, Michael Jones, Caroline Baynes, David J. Hunter, Mark S. Goldberg, Kristiina Aittomäki, Barbara Burwinkel, Jonathan Beesley, Maria Rossing, Norbert Arnold, Kathleen Claes, Renske Keeman, Esther M. John, John W.M. Martens, Katie M. O'Brien, Paolo Peterlongo, Mark H. Greene, Tracy A. O'Mara, Saundra S. Buys, Craig Luccarini, Atocha Romero, Paul A. James, Siddhartha Yadav, Zoe Steinsnyder, Diana Torres, Rudolf Kaaks, Camilla Wendt, Fabienne Lesueur, Ana Osorio, Olufunmilayo I. Olopade, Christopher A. Haiman, Agnes Jager, Tricia Lindstrom, Peter Devilee, Kristin K. Zorn, Loic Le Marchand, Darling J. Horcasitas, Michael Lush, Mark E. Robson, Jennifer T. Loud, Roger L. Milne, Lin Fritschi, Johanna I. Kiiski, Eric Hahnen, Jacques Simard, Annelie Augustinsson, Stig E. Bojesen, Kenneth Offit, Nadine Andrieu, Xiaohong R. Yang, Pooja Middha Kapoor, Joe Dennis, Beth N. Peshkin, Nadege Presneau, Darcy L. Thull, Fergus J. Couch, Gunnar Schmidt, Ute Hamann, Susan M. Domchek, Henrik Flyger, Mary B. Daly, Håkan Olsson, Clarice R. Weinberg, Niclas Håkansson, Elza Khusnutdinova, Inge Søkilde Pedersen, Manjeet K. Bolla, Steven N. Hart, Carl Blomqvist, Janet E. Olson, Maren T. Scheuner, Barbara Wappenschmidt, Marc Tischkowitz, Dominique Stoppa-Lyonnet, Nadine Tung, Stephen J. Chanock, Leslie Bernstein, Mikael Eriksson, José A. García-Sáenz, Jonathan Tyrer, Jose E. Castelao, Peter Kraft, Goska Leslie, Arto Mannermaa, Christopher G. Scott, Jacopo Azzollini, Eitan Friedman, Allison W. Kurian, Katarzyna Białkowska, Argyrios Ziogas, Hermann Brenner, Andrew K. Godwin, Patricia Harrington, Juliette Coignard, Daniele Campa, Susan L. Neuhausen, Marco Montagna, Marina Bermisheva, Alicja Wolk, Eric C. Polley, Abctb Investigators, and Daniel Barrowdale

Subjects
Adult, Genotype, media_common.quotation_subject, Science, Quantitative Trait Loci, General Physics and Astronomy, Breast Neoplasms, 02 engineering and technology, Brca1 brca2, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Linkage Disequilibrium, 03 medical and health sciences, Breast cancer, Cancer epidemiology, Humans, Genetic Predisposition to Disease, Author Correction, Cancer genetics, Alleles, 030304 developmental biology, media_common, BRCA2 Protein, 0303 health sciences, Multidisciplinary, BRCA1 Protein, Published Erratum, General Chemistry, Art, Middle Aged, 021001 nanoscience & nanotechnology, 3. Good health, Risk factors, Mutation, Female, 0210 nano-technology, Humanities, Genome-Wide Association Study
Abstract

Author(s): Coignard, Juliette; Lush, Michael; Beesley, Jonathan; O'Mara, Tracy A; Dennis, Joe; Tyrer, Jonathan P; Barnes, Daniel R; McGuffog, Lesley; Leslie, Goska; Bolla, Manjeet K; Adank, Muriel A; Agata, Simona; Ahearn, Thomas; Aittomaki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Arun, Banu K; Augustinsson, Annelie; Azzollini, Jacopo; Barrowdale, Daniel; Baynes, Caroline; Becher, Heko; Bermisheva, Marina; Bernstein, Leslie; Bialkowska, Katarzyna; Blomqvist, Carl; Bojesen, Stig E; Bonanni, Bernardo; Borg, Ake; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campa, Daniele; Carter, Brian D; Castelao, Jose E; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen BM; Clarke, Christine L; GEMO Study Collaborators; EMBRACE Collaborators; Collee, J Margriet; Conroy, Don M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Diez, Orland; Ding, Yuan Chun; Domchek, Susan M; Dork, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M; Dwek, Miriam; Eccles, Diana M; Eliassen, A Heather; Engel, Christoph; Eriksson, Mikael; Evans, D Gareth; Fasching, Peter A; Flyger, Henrik; Fostira, Florentia; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gago-Dominguez, Manuela; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; Garcia-Closas, Montserrat; Garcia-Saenz, Jose A; Gaudet, Mia M; Gayther, Simon A; Gehrig, Andrea; Georgoulias, Vassilios; Giles, Graham G; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E | Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.

Published
2021
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12. Breast Cancer Risk in Women from Ghana Carrying Rare Germline Pathogenic Mutations: A Resource for Genetic Counseling of West African Women

Author

Thomas U. Ahearn, Parichoy Pal Choudhury, Andriy Derkach, Beatrice Addai Wiafe, Baffour Awuah, Joel Yarney, Lawrence Edusei, Nicholas Titiloye, Verna Vanderpuye, Francis Aitpillah, Florence Dedey, Joseph Oppong, Ernest Osei-Bonsu, Máire Duggan, Louise A. Brinton, Craig Luccarini, Caroline Baynes, Alison M. Dunning, Brittny C. Davis Lynn, Stephen Chanock, Belynda Hicks, Meredith Yeager, Nilanjan Chatterjee, Richard Biritwum, Joe Nat Clegg-Lamptey, Kofi Nyarko, Seth Wiafe, Daniel Ansong, Douglas F. Easton, Jonine Figueroa, Montserrat Garcia-Closas, and Ghana Breast Health Study (GBHS)

Subjects
education.field_of_study, business.industry, Genetic counseling, Population, Absolute risk reduction, Cancer, medicine.disease, Institutional review board, Breast cancer, Relative risk, Medicine, skin and connective tissue diseases, business, education, CHEK2, Demography
Abstract

Background: Breast cancer risk estimates for women carrying germline mutations in breast cancer susceptibility genes are mainly based on studies of European ancestry women, with limited data for women in West African. Methods: We investigated associations between pathogenic variants in 34 putative susceptibility genes with breast cancer risk in 871 cases (307 estrogen receptor (ER)-positive, 321 ER-negative, and 243 ER-unknown) and 1,563 controls in a population-based study in Ghana, and estimated lifetime risk for mutation carriers in the general population. We compared results to those for European, Asian and African-American women. Findings: The frequency of pathogenic mutations in nine breast cancer genes (BRCA1, BRCA2, PALB2, TP53, ATM, BARD1, CHEK2, RAD51C, RAD52D) was 8·38% in cases and 1·22% in controls from GBHS. Mutations in BRCA1, BRCA2, PALB2, and TP53 were significantly associated with breast cancer risk at P

Published
2021
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14. Characterisation of protein-truncating and missense variants in

Author

Pei Sze, Ng, Rick Acm, Boonen, Eldarina, Wijaya, Chan Eng, Chong, Milan, Sharma, Sabine, Knaup, Shivaani, Mariapun, Weang Kee, Ho, Joanna, Lim, Sook-Yee, Yoon, Nur Aishah, Mohd Taib, Mee Hoong, See, Jingmei, Li, Swee Ho, Lim, Ern Yu, Tan, Benita Kiat-Tee, Tan, Su-Ming, Tan, Veronique Kiat-Mien, Tan, Rob Martinus, van Dam, Kartini, Rahmat, Cheng Har, Yip, Sara, Carvalho, Craig, Luccarini, Caroline, Baynes, Alison M, Dunning, Antonis, Antoniou, Haico, van Attikum, Douglas F, Easton, Mikael, Hartman, and Soo Hwang, Teo

Subjects
Male, Mice, Singapore, Malaysia, Animals, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Fanconi Anemia Complementation Group N Protein, Germ-Line Mutation
Abstract

Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.PTVs inDespite genetic and lifestyle differences between Asian and other populations, the population prevalence of

Published
2020

15. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author

Harald Surowy, Rulla M. Tamimi, Javier Benitez, Wing-Yee Lo, Celine M. Vachon, Nadege Presneau, John J. Spinelli, Ann Smeets, Hoda Anton-Culver, Veli-Matti Kosma, Christopher A. Haiman, Martha J. Shrubsole, Ross L. Prentice, Diana Eccles, Ursula Eilber, Loic Le Marchand, Katri Pylkäs, Jirong Long, Michael P. Lux, Sara Margolin, Hedy S. Rennert, Tom Maishman, Mary B. Daly, Rita K. Schmutzler, Julian Peto, Sune F. Nielsen, Eric Hahnen, Niclas Håkansson, Børge G. Nordestgaard, Mitul Shah, Matthias W. Beckmann, Anthony J. Swerdlow, Barbara Burwinkel, Rudolf Kaaks, Usha Menon, William J. Tapper, Argyrios Ziogas, Peter Hillemanns, Fares Al-Ejeh, Roger L. Milne, Wolfgang Janni, Pascal Guénel, Mikael Eriksson, Clarice R. Weinberg, Kyriaki Michailidou, Jonathan Beesley, Marike Gabrielson, J. Esteban Castelao, Margriet Collée, Janet E. Olson, Gad Rennert, Per Broberg, Rob A. E. M. Tollenaar, David Cox, Paolo Peterlongo, Helian Feng, Brian D. Carter, Nichola Johnson, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Kimberly F. Doheny, Paul L. Auer, Hans Wildiers, Jacques Simard, Michael Untch, Per Hall, Martine Dumont, Julie M. Cunningham, Thilo Dörk, Mary Beth Terry, Jenny Chang-Claude, Lang Wu, Irene L. Andrulis, Xiaohong R. Yang, Caroline Baynes, Isabel dos-Santos-Silva, Douglas F. Easton, Wei Shi, Emily Hallberg, Camilla Wendt, Hiltrud Brauch, Diana Torres, Olufunmilayo I. Olopade, David Van Den Berg, Georgia Chenevix-Trench, Alfons Meindl, Stig E. Bojesen, Jonine D. Figueroa, Dale P. Sandler, Vessela N. Kristensen, Christine L. Clarke, Wei Zheng, Manuela Gago-Dominguez, E Rozali, Henrik Flyger, Sheila Seal, Guanmengqian Huang, Marjanka K. Schmidt, Håkan Olsson, Christopher G. Scott, Kamila Czene, Laura Fachal, Rodney J. Scott, Jennifer Stone, Sara Y. Brucker, Qin Wang, David J. Hunter, Maya Ghoussaini, Christoph Engel, Keith Humphreys, Susan M. Gapstur, Daniel C. Tessier, Paolo Radice, John L. Hopper, Audrey Y. Jung, Lucy Xia, Atocha Romero, Chenjie Zeng, Peter A. Fasching, Jan Lubinski, Anna González-Neira, Nazneen Rahman, Robert N. Hoover, Thérèse Truong, Fergus J. Couch, Anna Marie Mulligan, Robert J. MacInnis, Ute Hamann, Hanne Meijers-Heijboer, Brigitte Rack, Simon S. Cross, Federico Canzian, J.-P. Meyer, Sara Lindström, Natalia Bogdanova, Trinidad Caldés, Olivia Fletcher, Peter Kraft, Elinor J. Sawyer, Alexander Gusev, Louise A. Brinton, Diether Lambrechts, Bingshan Li, Kristan J. Aronson, Jane Romm, Anja Rudolph, Peter Devilee, Qiuyin Cai, Arto Mannermaa, Elad Ziv, Alice S. Whittemore, Abigail Thomas, Hermann Brenner, Montserrat Garcia-Closas, Patrick Neven, Kristine Jones, Miriam Dwek, Sibylle Loibl, Heli Nevanlinna, Jolanta Lissowska, Susan L. Neuhausen, Elza Khusnutdinova, Marina Bermisheva, Alicja Wolk, Lin Fritschi, Xingyi Guo, Angela Cox, Michael Jones, Xiaoqing Chen, Esther M. John, Richard Barfield, Volker Arndt, Patricia Harrington, Quinten Waisfisz, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Stacey L. Edwards, Melissa C. Southey, Andreas Schneeweiss, Jack A. Taylor, Robert Winqvist, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Kathrin Thöne, Dieter Flesch-Janys, Mark S. Goldberg, Craig Luccarini, Sten Cornelissen, Jingmei Li, Michael J. Kerin, Myrto Barrdahl, Xiao-Ou Shu, Alison M. Dunning, Manjeet K. Bolla, Carl Blomqvist, Graham G. Giles, Hans Christiansen, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Belynda Hicks, Ivana Maleva Kostovska, Tongguang Cheng, Yingchang Lu, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Medical Oncology, Guo, Xingyi [0000-0001-5269-1294], Al-Ejeh, Fares [0000-0002-1553-0077], Li, Bingshan [0000-0003-2129-168X], Gusev, Alexander [0000-0002-7980-4620], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Brauch, Hiltrud [0000-0001-7531-2736], Collée, Margriet [0000-0002-9272-9346], Cox, Angela [0000-0002-5138-1099], Cunningham, Julie M [0000-0002-8159-3025], Fachal, Laura [0000-0002-7256-9752], Fletcher, Olivia [0000-0001-9387-7116], Hein, Alexander [0000-0003-2601-3398], Hicks, Belynda [0000-0001-8014-4888], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Khusnutdinova, Elza [0000-0003-2987-3334], Li, Jingmei [0000-0001-8587-7511], Menon, Usha [0000-0003-3708-1732], Nevanlinna, Heli [0000-0002-0916-2976], Nordestgaard, Børge G [0000-0002-1954-7220], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher G [0000-0003-1340-0647], Shrubsole, Martha J [0000-0002-5591-7575], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul DP [0000-0001-8494-732X], Milne, Roger L [0000-0001-5764-7268], Easton, Douglas F [0000-0003-2444-3247], Zheng, Wei [0000-0003-1226-070X], Apollo - University of Cambridge Repository, Human Genetics, and ARD - Amsterdam Reproduction and Development

Subjects
0301 basic medicine, Risk, medicine.medical_specialty, Gene Expression, Genome-wide association study, Breast Neoplasms, Biology, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Genetic model, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic association, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Expression quantitative trait loci, Medical genetics, Female, Gene expression, Breast Cancer Genetics, Genome-Wide Association Study
Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P −6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

Published
2019
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16. Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author

Maya Ghoussaini, Stacey L. Edwards, Kyriaki Michailidou, Silje Nord, Richard Cowper-Sal·lari, Kinjal Desai, Siddhartha Kar, Kristine M. Hillman, Susanne Kaufmann, Dylan M. Glubb, Jonathan Beesley, Joe Dennis, Manjeet K. Bolla, Qin Wang, Ed Dicks, Qi Guo, Marjanka K. Schmidt, Mitul Shah, Robert Luben, Judith Brown, Kamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Diether Lambrechts, Bernard Thienpont, Patrick Neven, Hans Wildiers, Annegien Broeks, Laura J. Van’t Veer, Emiel J. Th Rutgers, Fergus J. Couch, Janet E. Olson, Emily Hallberg, Celine Vachon, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Julian Peto, Isabel dos-Santos-Silva, Lorna Gibson, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji-Yeob Choi, Sue K. Park, Dong-Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Anna H. Wu, Chiu-chen Tseng, David Van Den Berg, Daniel O. Stram, Javier Benitez, M Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Qiuyin Cai, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Annika Lindblom, Sara Margolin, Soo Hwang Teo, Cheng Har Yip, Daphne S. C. Lee, Tien Y. Wong, Maartje J. Hooning, John W. M. Martens, J. Margriet Collée, Carolien H. M. van Deurzen, John L. Hopper, Melissa C. Southey, Helen Tsimiklis, Miroslav K. Kapuscinski, Chen-Yang Shen, Pei-Ei Wu, Jyh-Cherng Yu, Shou-Tung Chen, Grethe Grenaker Alnæs, Anne-Lise Borresen-Dale, Graham G. Giles, Roger L. Milne, Catriona McLean, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Shaik Ahmad Bin Syed Buhari, Yik Ying Teo, Peter A. Fasching, Lothar Haeberle, Arif B. Ekici, Matthias W. Beckmann, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Koto, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Thilo Dörk, Natalia V. Bogdanova, Sonja Helbig, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Peter Devilee, Robert A. E. M. Tollenaar, Caroline Seynaeve, Christi J. Van Asperen, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Susan Slager, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Ute Hamann, Diana Torres, Wei Zheng, Jirong Long, Hoda Anton-Culver, Susan L. Neuhausen, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S. Healey, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Nuria Álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Ines de Santiago, Jason Carroll, Carlos Caldas, Melissa A. Brown, Mathieu Lupien, Vessela N. Kristensen, Paul D. P. Pharoah, Georgia Chenevix-Trench, Juliet D. French, Douglas F. Easton, and Alison M. Dunning

Subjects
Oncology, medicine.medical_specialty, Multidisciplinary, business.industry, Published Erratum, MEDLINE, General Physics and Astronomy, Locus (genetics), General Chemistry, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, medicine, 030212 general & internal medicine, business
Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10−43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology., Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

Published
2018

17. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia

Author

Wei Xiong Wen, Jamie Allen, Kah Nyin Lai, Shivaani Mariapun, Siti Norhidayu Hasan, Pei Sze Ng, Daphne Shin-Chi Lee, Sheau Yee Lee, Sook-Yee Yoon, Joanna Lim, Shao Yan Lau, Brennan Decker, Karen Pooley, Leila Dorling, Craig Luccarini, Caroline Baynes, Don M Conroy, Patricia Harrington, Jacques Simard, Cheng Har Yip, Nur Aishah Mohd Taib, Weang Kee Ho, Antonis C Antoniou, Alison M Dunning, and Douglas F

Published
2018
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18. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author

Vesa Kataja, Aida Karina Dieffenbach, Chia-Ni Hsiung, Catherine S. Healey, Gie Hooi Tan, Soo Hwang Teo, Domenico Palli, Frederik Marme, Katri Pylkäs, Roger L. Milne, Jaana M. Hartikainen, Gord Glendon, Susan L. Slager, Chen-Yang Shen, Fredrick R. Schumacher, Daniel F. Schmidt, Suleeporn Sangrajrang, Kee Seng Chia, Lorna Gibson, Pascal Guénel, Alice S. Whittemore, Jenny Chang-Claude, Yu Tang Gao, Hidemi Ito, Simon S. Cross, Sofia Khan, Marie Sanchez, Daniel Vincent, Daniel Herrero, Nicola Miller, Antoinette Hollestelle, Caroline M. Seynaeve, Christopher A. Haiman, Hermann Brenner, Kay-Tee Khaw, Loris Bernard, Habibul Ahsan, Melissa C. Southey, David Van Den Berg, Martha J. Shrubsole, Daniel O. Stram, William Blot, Mel Maranian, Robert Winqvist, Keitaro Matsuo, John W. M. Martens, Heli Nevanlinna, Mia M. Gaudet, Anna Jakubowska, Christine D. Berg, Paul D.P. Pharoah, Jacques Simard, Manjeet K. Bolla, Dieter Flesch-Janys, Mark S. Goldberg, Paul Brennan, Ching Wan Chan, Sune F. Nielsen, Sara Lindström, Mitul Shah, Matthias W. Beckmann, Craig Luccarini, Jonathan Beesley, Kyriaki Michailidou, Paolo Peterlongo, Marc J. Gunter, Anna González-Neira, Ji Yeob Choi, Per Hall, Sarah Stewart-Brown, Keith Humphreys, Hui Cai, Kathleen E. Malone, Elinor J. Sawyer, Louise A. Brinton, Marjanka K. Schmidt, Xiao-Ou Shu, Barbara Perkins, Lotte Maxild Mortensen, Chiu-Chen Tseng, Hanne Meijers-Heijboer, Minouk J. Schoemaker, Keun-Young Yoo, Julia A. Knight, Alan Ashworth, Stig E. Bojesen, Kamila Czene, Artitaya Lophatananon, Graham G. Giles, S. Ahmed, Kazuo Tajima, Douglas F. Easton, Maria Kabisch, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Irene L. Andrulis, Clare Turnbull, Caroline Baynes, Christine B. Ambrosone, Jan Lubinski, Muriel A. Adank, A. Meindl, Taru A. Muranen, Siranoush Manoukian, Susan M. Gapstur, Natalia Bogdanova, Alexander Hein, Annika Lindblom, Nazneen Rahman, Annegien Broeks, Lothar Haeberle, Federico Canzian, G Pita, Ming-Feng Hou, Hiroji Iwata, Drakoulis Yannoukakos, Diana Torres, Vessela N. Kristensen, Peter Devilee, Qiuyin Cai, Christi J Asperen, John L. Hopper, Diether Lambrechts, Michael Lush, Hans Wildiers, Joe Dennis, Sandra L. Halverson, Carl Blomqvist, Erik Van Limbergen, Malin Sund, Daehee Kang, Grethe I. Grenaker Alnæs, Marilie D. Gammon, Ursula Eilber, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Kirsimari Aaltonen, Olivia Fletcher, Jonine D. Figueroa, Angela Cox, Pei Ei Wu, Maartje J. Hooning, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Malcolm W.R. Reed, Emily Hallberg, Sara Margolin, Volker Arndt, Montserrat Garcia-Closas, Francois Bacot, Rita K. Schmutzler, Julian Peto, David J. Hunter, Thomas Brüning, Katarzyna Jaworska, Christof Sohn, Børge G. Nordestgaard, Enes Makalic, Hatef Darabi, Barbara Burwinkel, Petra P.H. Peeters, J. Margriet Collée, Rongxi Yang, Robert N. Hoover, Eiliv Lund, Fergus J. Couch, Ute Hamann, Jirong Long, Wei Zheng, Sabine Behrens, Giske Ursin, Muhammad G. Kibriya, Claire Mulot, Laure Dossus, Helen Tsimiklis, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Alison M. Dunning, Lisa B. Signorello, Valerie Gaborieau, Kenneth Muir, Anthony J. Swerdlow, Javier Benitez, Judith S. Brand, Sander Canisius, Hoda Anton-Culver, Veli-Matti Kosma, Thilo Dörk, Sten Cornelissen, Christa Stegmaier, Cheng Har Yip, Brian E. Henderson, Harald Surowy, Jingmei Li, Nur Aishah Taib, W. Ryan Diver, Carmel Apicella, Janet E. Olson, Kristiina Aittomäki, Celine M. Vachon, Regina M. Santella, Dimitrios Trichopoulos, Jianjun Liu, Nick Orr, Martine Dumont, Christian Sutter, Sue K. Park, Mikael Hartman, Susan L. Neuhausen, Hui Miao, M. Pilar Zamora, Anna H. Wu, Rob B. van der Luijt, Isabel dos-Santos-Silva, Graham Casey, Henrik Flyger, M. Rosario Alonso, Nuria Álvarez, Michael J. Kerin, Loic Le Marchand, Jose Ignacio Arias Perez, Mikael Eriksson, Esther M. John, Quinten Waisfisz, Qin Wang, Daniel C. Tessier, Paolo Radice, Robert A.E.M. Tollenaar, James McKay, Silje Nord, Hiltrud Brauch, José María Huerta, Stephen J. Chanock, Mervi Grip, Patrick Neven, Senno Verhoef, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, and CCA - Oncogenesis

Subjects
Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, Cohort Studies, brca1, Breast cancer, Research Support, N.I.H., Extramural, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, common variants, Journal Article, estrogen, chek2-asterisk-1100delc, Genetics, medicine, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Non-U.S. Gov't, genotype imputation, risk, Genetic association, Research Support, Non-U.S. Gov't, Chromatin binding, Extramural, Cancer, Microarray Analysis, confer susceptibility, medicine.disease, 3. Good health, ovarian-cancer, Genetic Loci, Case-Control Studies, alleles, Female, Imputation (genetics), Genome-Wide Association Study, metaanalysis
Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼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 < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

Published
2015
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19. Low risk of invasive lobular carcinoma of the breast in carriers of BRCA1 (hereditary breast and ovarian cancer) and TP53 (Li-Fraumeni syndrome) germline mutations

Author

Yolla El Dakdouki, Julia Salleron, Yoan Ditchi, Pernelle Lavaud, Marie-Christine Mathieu, Chloé Broudin, Patrick R. Benusiglio, Donia Lejri, Caroline Baynes, Marie Muller, Olivier Caron, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, University of Cambridge [UK] (CAM), Département de biologie et pathologie médicales [Gustave Roussy], Unité fonctionnelle d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Oncology, medicine.medical_specialty, Heterozygote, endocrine system diseases, [SDV]Life Sciences [q-bio], Genetic counseling, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Internal medicine, Internal Medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Li-Fraumeni syndrome, TP53, skin and connective tissue diseases, education, Germ-Line Mutation, BRCA2 Protein, education.field_of_study, business.industry, BRCA1 Protein, Cancer, BRCA1, medicine.disease, BRCA2, 3. Good health, genetic susceptibility to disease, body regions, Carcinoma, Lobular, Carcinoma, Intraductal, Noninfiltrating, Li–Fraumeni syndrome, 030220 oncology & carcinogenesis, Invasive lobular carcinoma, invasive lobular carcinoma of the breast, Surgery, Female, Tumor Suppressor Protein p53, Ovarian cancer, business
Abstract

International audience; BACKGROUND:Invasive lobular carcinoma (ILC) of the breast has epidemiological, molecular and clinical specificities, and should likely be considered a unique entity. As for genetic susceptibility, CDH1 germline mutations predispose exclusively to ILC. Data are however scarce regarding ILC in women with BRCA1/2 (Hereditary Breast and Ovarian Cancer) and TP53 (Li-Fraumeni syndrome) germline mutations.METHODS:We included all breast cancers from female patients tested at our institute between 1992 and 2016 (n = 3469) for which pathology data were available. ILC proportion comparison according to mutational status was performed by a chi-squared test. The impact of susceptibility genes on ILC proportion was investigated by univariate logistic regression with wild-type patients as reference.RESULTS AND DISCUSSION:There were 265 (7.64%) ILC: 2/342 (0.58%) in BRCA1 patients, 24/238 (10%) in BRCA2 patients, 1/57 (1.75%) in TP53 patients and 238/2832 (8.4%) in non-carriers. The majority of breast cancers in all groups were invasive ductal and ductal in situ carcinomas. The difference in ILC proportion was highly significant (P < 0.001). Compared to wild-type patients, BRCA1 was associated with a lower ILC proportion (OR 0.064 [95% CI 0.016;0.259], P < 0.0001). BRCA2 OR was 1.222 [95%CI 0.785;1.902] (P = 0.374), TP53 OR was 0.195 [95%CI 0.027;1.412] (P = 0.105). ILC are therefore underrepresented in BRCA1 and TP53 mutation carriers. Formal significance (P = 0.05) was not reached for TP53, but statistical power was only 38%. Based on ILC incidence in the general population, we make the hypothesis that BRCA1 and TP53 do not predispose to ILC, as the few occurrences of ILC in mutation carriers could be attributed to chance and not to germline mutations. Our observations will be useful to clinical cancer geneticists managing patients with ILC, as a BRCA1 or TP53 mutation in these patients would be unlikely. Genetic counseling should be adapted accordingly.

Published
2017
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20. Association analysis identifies 65 new breast cancer risk loci

Author

Michael Jones, Dong-Young Noh, Martha J. Shrubsole, Chen-Yang Shen, Xiaoqing Chen, Esther M. John, Patricia Harrington, Quinten Waisfisz, Sue K. Park, Miriam Dwek, Christa Stegmaier, Sibylle Loibl, Wing-Yee Lo, Suleeporn Sangrajrang, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Keun-Young Yoo, Arja Jukkola-Vuorinen, Kathrin Thöne, James McKay, John J. Spinelli, Brian D. Carter, Elza Khusnutdinova, Francois Bacot, Paul L. Auer, Anna H. Wu, Christopher I. Amos, Johanna I. Kiiski, Hans Wildiers, Manjeet K. Bolla, Soo Hwang Teo, Julie M. Cunningham, Zhaoming Wang, Dieter Flesch-Janys, Argyrios Ziogas, Ann Smeets, Min Hyuk Lee, Xiaohong R. Yang, Carl Blomqvist, Natalia Antonenkova, Vassilios Georgoulias, Siranoush Manoukian, Anne Lise Børresen-Dale, Montserrat Garcia-Closas, Priyanka Sharma, Michael J. Kerin, Loic Le Marchand, Yoshio Kasuga, Michael Untch, Thomas Brüning, Natalia Bogdanova, Juliet D. French, Mark E. Sherman, Diana Eccles, Don M. Conroy, Marcia Adams, Pascal Guénel, Jonine D. Figueroa, Somchai Thanasitthichai, Jonathan Beesley, Paolo Peterlongo, Angela Cox, Graham G. Giles, Hans Christiansen, Irene L. Andrulis, Caroline Baynes, V. Shane Pankratz, Kristine Jones, Wei Zheng, Motoki Iwasaki, Rita K. Schmutzler, Julian Peto, Sara Margolin, Hedy S. Rennert, Hidemi Ito, Caroline Seynaeve, Jirong Long, Rachel Lloyd, Mark S. Goldberg, Javier Benitez, Børge G. Nordestgaard, Kathleen E. Malone, A. Heather Eliassen, Valerie Rhenius, Kristan J. Aronson, Maartje J. Hooning, Ursula Eilber, Christopher A. Haiman, Ji Yeob Choi, Jaana M. Hartikainen, Ian W. Brock, Barbara Burwinkel, Brigitte Rack, Mitul Shah, Matthias W. Beckmann, Belynda Hicks, Bernardo Bonanni, Alexander Hein, Leslie Bernstein, Christine L. Clarke, Emilie Cordina-Duverger, Sabine Behrens, Hoda Anton-Culver, Angela Brooks-Wilson, Bin Zhu, Gord Glendon, Banu Arun, José A. García-Sáenz, Jose Ignacio Arias Perez, Anne Grundy, Ans M.W. van den Ouweland, Nadege Presneau, Volker Arndt, Mikael Eriksson, Simon S. Cross, Craig Luccarini, Anthony J. Swerdlow, Veli-Matti Kosma, Hui Miao, Ming-Feng Hou, Hiroji Iwata, Christi J. van Asperen, Henrik Flyger, Jennifer Stone, Qin Wang, Penny Soucy, Heli Nevanlinna, Jane Heyworth, Shoichiro Tsugane, Annika Lindblom, Curtis Olswold, Trinidad Caldés, Laura Fachal, Ed Dicks, Shirley Hui, Katja Butterbach, Alison M. Dunning, Peter Devilee, Qiuyin Cai, Antonis C. Antoniou, Diether Lambrechts, Katarzyna Kaczmarek, Katri Pylkäs, Fredrick R. Schumacher, Arif B. Ekici, Aaron D. Norman, Jolanta Lissowska, Daniel C. Tessier, N Hamel, Paolo Radice, Håkan Olsson, Vessela N. Kristensen, Ling Tong, Harald Surowy, Rulla M. Tamimi, Jonathan Tyrer, Michael P. Lux, Stacey L. Edwards, Kathryn J. Ruddy, Giske Ursin, Myrto Barrdahl, Xiao-Ou Shu, Primitiva Menéndez, Sara Y. Brucker, Elad Ziv, Kenneth Muir, Eric Hahnen, Andy C. H. Lee, Rodney J. Scott, Lothar Haeberle, Darya Prokofyeva, Isabel dos-Santos-Silva, Peter Kraft, David G. Cox, Jong Won Lee, Sunil R. Lakhani, Kelly-Anne Phillips, Douglas F. Easton, Melissa C. Southey, Jan Lubinski, Jose E. Castelao, Hanne Meijers-Heijboer, Ivana Maleva Kostovska, Siddhartha Kar, Renske Keeman, Celine M. Vachon, Diana Torres, Stephen J. Chanock, Jack A. Taylor, Emiel J. Th. Rutgers, Chuen Neng Lee, Jason Vollenweider, Gadi Rennert, Jane Romm, Amy E. McCart Reed, Kee Seng Chia, Thomas Rüdiger, Anja Rudolph, Catriona McLean, David Van Den Berg, Christopher G. Scott, Mervi Grip, Lucy Xia, Georgia Chenevix-Trench, Robert Winqvist, Mary Beth Terry, Jenny Chang-Claude, Hans-Ulrich Ulmer, Mikael Hartman, Dona N. Ho, Maria Kabisch, Christoph Engel, Claire Mulot, Grethe I. Grenaker Alnæs, Arto Mannermaa, Nazneen Rahman, Tjoung-Won Park-Simon, Atocha Romero, Lin Fritschi, Manuela Gago-Dominguez, Matthias Ruebner, Valerie Gaborieau, Keitaro Matsuo, Asha Rostamianfar, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, J.-P. Meyer, Sara Lindström, Annegien Broeks, Audrey Lemaçon, Tsun Leung Chan, Tongguang Cheng, Robert J. MacInnis, Habibul Ahsan, Federico Canzian, Paul Brennan, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Jacek Gronwald, Sung-Won Kim, Daehee Kang, Daniel O. Stram, Nichola Johnson, Rob B. van der Luijt, Sten Cornelissen, Camilla Wendt, Dylan M. Glubb, Olufunmilayo I. Olopade, Usha Menon, David J. Hunter, Kristiina Aittomäki, Jamie Allen, Chiu-Chen Tseng, Keith Humphreys, Edmond S. K. Ma, Peter Hillemanns, Hiltrud Brauch, Chia-Ni Hsiung, Sheila Seal, Junko Ishiguro, Dale P. Sandler, Peter Schürmann, Gary D. Bader, Sarah Stewart-Brown, Flavio Lejbkowicz, Marike Gabrielson, Wolfgang Janni, Judith S. Brand, Jingmei Li, Ava Kwong, Stig E. Bojesen, Ying Zheng, Mila Pinchev, Yu Tang Gao, Susan E. Hankinson, Elinor J. Sawyer, Per Broberg, Sofia Khan, Grace Sheng, Alfons Meindl, Margriet Collée, Jyh-Cherng Yu, Ute Krüger, Louise A. Brinton, Elizabeth W. Pugh, Thilo Dörk, Hilary K. Finucane, Peter A. Fasching, Shan Wang-Gohrke, Jenna Lilyquist, Muriel A. Adank, Marjanka K. Schmidt, Susan M. Gapstur, Sune F. Nielsen, Maya Ghoussaini, Minouk J. Schoemaker, Roger L. Milne, Jacques Simard, Clarice R. Weinberg, Kyriaki Michailidou, Shivaani Mariapun, Rob A. E. M. Tollenaar, Lizet E. van der Kolk, Nicola Miller, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Ross L. Prentice, Anna Marie Mulligan, Jason S. Carroll, Taiki Yamaji, Carolina Ellberg, Mingajeva Elvira, Olivia Fletcher, Arnaud Droit, Per Hall, Maria Elena Martinez, Maria Tengström, Hui Cai, Xia Jiang, Janet E. Olson, Julia A. Knight, Nick Orr, Angel Carracedo, Guanmengqian Huang, Martine Dumont, Cheng Har Yip, Tom Maishman, Mary B. Daly, Artitaya Lophatananon, Niclas Håkansson, Steven N. Hart, Nur Aishah Taib, Andreas Schneeweiss, Daniel F. Schmidt, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Rudolf Kaaks, Karen McCue, Enes Makalic, Kimberly F. Doheny, Eunjung Lee, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Alice S. Whittemore, Hermann Brenner, Lorraine Durcan, Kamila Czene, Patrick Neven, John L. Hopper, Clinical Genetics, Medical Oncology, Human Genetics, CCA - Cancer biology and immunology, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Allen, Jamie [0000-0002-8677-2225], Fachal Vilar, Laura [0000-0002-7256-9752], Carroll, Jason [0000-0003-3643-0080], Rhenius, Valerie [0000-0003-4215-3235], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, Regulatory Sequences, Nucleic Acid, skin and connective tissue diseases, Cancer genetics, Genetics, Multidisciplinary, medicine.diagnostic_test, 3. Good health, Europe, annotation, Medical genetics, Female, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, architecture, European Continental Ancestry Group, ABCTB Investigators, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, White People, NBCS Collaborators, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Genetic variation, ConFab/AOCS Investigators, expression, medicine, Genetic predisposition, Journal Article, Humans, Computer Simulation, Genetic Predisposition to Disease, biological pathways, Genetic association, Genetic testing, Genetic association study, Binding Sites, interaction networks, medicine.disease, comprehensive molecular portraits, mutations, susceptibility loci, 030104 developmental biology, Genetic Loci, genome-wide association, protein, Transcription Factors, Genome-Wide Association Study
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

Published
2017
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21. A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

Author

Christopher J. Talbot, Ana Vega, Paul D.P. Pharoah, Caroline Baynes, John Yarnold, Craig Luccarini, Laura Fachal, Rebecca Elliott, Sarah L. Gulliford, Kyriaki Michailidou, Matthew R. Sydes, Barry S. Rosenstein, Jonathan Tyrer, Jennifer Titley, Søren M. Bentzen, Catharine M L West, Alison M. Dunning, Deborah J. Thompson, Don M. Conroy, Charlotte E. Coles, Leila Dorling, Emma Hall, Rebecca Mayes, George A. Tanteles, Mel Maranian, Joanne S Haviland, Gillian C. Barnett, Neil G. Burnet, Radka Platte, Vivek Misra, Jennifer S. Wilkinson, Paul Symonds, Joe Dennis, David P. Dearnaley, Antonio Gómez-Caamaño, and Sarah L. Kerns

Subjects
Male, Oncology, medicine.medical_specialty, Pathology, Genotype, Radiogenomics, Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Gene Frequency, Internal medicine, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, Radiology, Nuclear Medicine and imaging, Prospective Studies, Radiation Injuries, Prospective cohort study, Allele frequency, Radiotherapy, Adverse effects, business.industry, Genetic Variation, Prostatic Neoplasms, Cancer, Dose-Response Relationship, Radiation, Hematology, medicine.disease, Female, Radiotherapy, Adjuvant, Radiotherapy, Intensity-Modulated, Late toxicity, business, Genome-wide association scan, Genome-Wide Association Study
Abstract

Background and purpose This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. Materials and methods A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. Results Quantile–quantile plots show more associations at the P −7 level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients . However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. Conclusions This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.

Published
2014
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22. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

Author

Melissa C. Southey, Qin Wang, Paolo Radice, Robert Winqvist, Vesa Kataja, Anna Jakubowska, Audrey Lemaçon, Elinor J. Sawyer, Hermann Brenner, Pascal Guénel, Heli Nevanlinna, Judith S. Brand, Patrick Neven, Mark S. Goldberg, Jan Lubinski, P. D. P Pharoah, Sara Margolin, Vessela N. Kristensen, Bernardo Bonanni, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Anne Lise Børresen-Dale, Natalia Bogdanova, Marjanka K. Schmidt, Thilo Dörk, Grethe I. GrenakerAlnæs, Wei Zheng, Celine M. Vachon, Diether Lambrechts, Isabel dos-Santos-Silva, Alison M. Dunning, Annegien Broeks, Douglas F. Easton, Javier Benitez, Michael Jones, Hoda Anton-Culver, Véronique Adoue, Sander Canisius, Roger L. Milne, Ans M.W. van den Ouweland, Yosr Hamdi, Mel Maranian, Angela Cox, Aocs Investigators, Maartje J. Hooning, Dijana Plaseska-Karanfilska, Frederik Marmé, Volker Arndt, Simon S. Cross, Silje Nord, Stig E. Bojesen, Kyriaki Michailidou, Penny Soucy, Joe Dennis, Hiltrud Brauch, Anja Rudolph, Rob A. E. M. Tollenaar, Arto Mannermaa, Maria Kabisch, Christopher A. Haiman, Susan L. Neuhausen, Loic Le Marchand, Katri Pylkäs, Irene L. Andrulis, Xiao-Ou Shu, Caroline Baynes, kConFab, Peter Devilee, Georgia Chenevix-Trench, Annika Lindblom, Emily Hallberg, Diana Torres, Anthony J. Swerdlow, Graham G. Giles, Jenny Chang-Claude, Lothar Haeberle, Tomi Pastinen, Curtis Olswold, Peter A. Fasching, Montserrat Garcia-Closas, Manjeet K. Bolla, Carl Blomqvist, Mikael Eriksson, Henrik Flyger, Kamila Czene, John L. Hopper, Fergus J. Couch, Ute Hamann, Jacques Simard, Arnaud Droit, Per Hall, Jonine D. Figueroa, Hatef Darabi, Julian Peto, Barbara Burwinkel, Canadian Institutes of Health Research, Norwegian Regional Health authorities, Cancer Research UK (Reino Unido), Unión Europea, United States of Department of Health & Human Services, Post-Cancer GWAS initiative, KWF Kankerbestrijding, Instituto de Salud Carlos III, California Breast Cancer Research Program, California Department of Public Health, Federal Ministry of Education & Research (Alemania), Finlands Akademi (Finlandia), United States Army Medical Research and Development Command, Stichting tegen Kanker, Deutsche Krebshilfe, Fondazione IRCCS Istituto Nazionale Tumori, National Health and Medical Research Council (Australia), Ministère du Développement économique, de Innovation et de Exportation (Canadá), The Research Council of Norway, Southern and Eastern Norway Regional Health Authority, Norwegian Cancer Society, Biobanking and BioMolecular resources Research Infrastructure (Países Bajos), Yorkshire Cancer Research, BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology, Agency for Science, Technology and Research (Singapur), NIH - National Cancer Institute (NCI). Specialized Programs of Research Excellence (SPOREs) (Estados Unidos), Medical Oncology, Clinical Genetics, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Canadian Institutes of Health Research (CIHR), Cancer Research UK, European Union (EU), United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Instituto de Salud Carlos III - ISCIII, California Breast Cancer Research Fund, Federal Ministry of Education & Research (BMBF), Academy of Finland, U.S. Army Medical Research & Materiel Command (USAMRMC), National Health and Medical Research Council of Australia, Ministry of Economic Development, Innovation and Export Trade, Research Council of Norway, South Eastern Norway Health Authority, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), Agency for Science Technology & Research (ASTAR), and Specialized Program of Research Excellence (SPORE) in Breast Cancer

Subjects
0301 basic medicine, Genome-wide association study, chromatin features, ANALYSES REVEAL, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Risk Factors, Odds Ratio, Medicine, CONFER SUSCEPTIBILITY, health care economics and organizations, Genetics, COMMON VARIANTS, 3. Good health, Multicenter Study, Europe, Phenotype, Oncology, association studies, 030220 oncology & carcinogenesis, Female, Chromosomes, Human, Pair 4, Canada, Quantitative Trait Loci, Single-nucleotide polymorphism, DNA-DAMAGE RESPONSE, MISSENSE SUBSTITUTIONS, Breast Neoplasms, cis-regulatory variants, Quantitative trait locus, News, Polymorphism, Single Nucleotide, Risk Assessment, OVARIAN-CANCER, Mitochondrial Proteins, 03 medical and health sciences, Breast cancer, breast cancer, SDG 3 - Good Health and Well-being, Biomarkers, Tumor, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, FUNCTIONAL VARIANTS, Gene, Genetic Association Studies, Genetic association, genome-wide association study, business.industry, HUMAN-CELLS, DNA Helicases, Cancer, medicine.disease, susceptibility loci, 030104 developmental biology, Case-Control Studies, differential allelic expression, enhancer, business, Carrier Proteins, BRCA1 MUTATION CARRIERS, Priority Research Paper, genetic susceptibility
Abstract

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas. This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program - grant # CRN-87521, the Ministry of Economy Innovation and Exportations-grant # PSR-SIIRI-701 and by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, and the Ministere de l'Economie, de la Science et de l'Innovation du Quebec through Genome Quebec and The Quebec Breast Cancer Foundation for the PERSPECTIVE project. Jacques Simard is Chairholder of the Canada Research Chair in Oncogenetics. Silje Nord is financed by a carrier grant from the Norwegian Regional Health authorities (Grant number 2014061). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]; BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Center. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070). The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supportd by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS was financilly supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and and Bert von Kantzows foundation. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG (Milan Breast Cancer Study Group) is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000"). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program - grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701. The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A-L Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale and 27208 to V.N. Kristensen) and the Norwegian Cancer Society (to A-L Borresen-Dale and 419616 - 71248 - PR-2006-0282 to V.N. Kristensen). It has received funding from the K.G. Jebsen Centre for Breast Cancer Research (2012-2015). The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Marit and Hans Rausings Initiative against Breast Cancer. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. SEARCH is funded by a programme grant from Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. Sí

Published
2016
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23. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

Author

Artitaya Lophatananon, W. Ryan Diver, Stig E. Bojesen, Roman Corral, Fredrick R. Schumacher, Stephen J. Chanock, Shannon K. McDonnell, Graham G. Giles, Craig C. Teerlink, Douglas F. Easton, Cezary Cybulski, Brian E. Henderson, Judith A. Clements, Ali Amin Al Olama, Francois Bacot, David P. Dearnaley, Elio Riboli, Peter Klarskov, Daniel Vincent, Rosemary A. Wilkinson, Danielle M. Karyadi, Michelle Guy, Vincent Khoo, Christopher A. Haiman, Afshan Siddiq, M. Andreas Røder, Amit Joshi, Jong Y. Park, Walther Vogel, Henrik Grönberg, Angela Cox, Rudolf Kaaks, Nora Pashayan, Timothy J. Key, C. R. J. Woodhouse, Jarmo Virtamo, Meredith Yeager, Malgorzata Tymrakiewicz, Sune F. Nielsen, Richard B. Hayes, Johanna Schleutker, Gianluca Severi, Robert Huddart, Wei Zheng, Thomas A. Sellers, Melanie Maranian, Shahana Ahmed, David E. Neal, Daniel Leongamornlert, Zsofia Kote-Jarai, Tiina Wahlfors, Loic Le Marchand, Kay-Tee Khaw, Tokhir Dadaev, Lisa A. Cannon-Albright, Janet L. Stanford, William J. Blot, Andy C. H. Lee, Freddie C. Hamdy, Siqun L. Zheng, Rosalind A. Eeles, Alison M. Dunning, Mariana C. Stern, Melissa C. Southey, Don M. Conroy, Kenneth Muir, Ahva Shahabi, Alan Horwich, Gerald L. Andriole, Antje E. Rinckleb, Srilakshmi Srinivasan, Tim Dudderidge, Joe Dennis, Radka Kaneva, Vanio Mitev, Angela Morgan, Sue A. Ingles, Adam S. Kibel, Markus Aly, Koveela Govindasami, Maya Ghoussaini, Jenny L Donovan, Manuel R. Teixeira, Emma J. Sawyer, Sara Lindström, Jiangfeng Xu, Maren Weischer, Ed Dicks, Jyotsna Batra, S Jugurnauth-Little, Hui-Yi Lin, Suzanne Kolb, Lisa B. Signorello, Dallas R. English, Antonis C. Antoniou, Federico Canzian, Anssi Auvinen, Mia M. Gaudet, Paula Paulo, Paul D.P. Pharoah, Heiko Müller, Qiuyin Cai, Børge G. Nordestgaard, Esther M. John, Sonja I. Berndt, D J Schaid, Daniele Campa, Chris Ogden, Colin Cooper, Craig Luccarini, Jan Lubinski, Elaine A. Ostrander, Ruth C. Travis, Dominika Wokołorczyk, John L. Hopper, Sofia Maia, Sara Benlloch, Chris Parker, Erika M. Kwon, Nicholas van As, Caroline Baynes, C. Slavov, Teuvo L.J. Tammela, Ethan M. Lange, Daniel C. Tessier, David J. Hunter, Dietrich Rothenbacher, Robert A. Stephenson, Liesel M. FitzGerald, Christiane Maier, Hermann Brenner, Kathleen A. Cooney, Graham A. Colditz, Felicity Lose, Edward J. Saunders, Demetrius Albanes, Stephen N. Thibodeau, Fredrik Wiklund, Amanda B. Spurdle, Jan Adolfsson, Susan M. Gapstur, Peter Kraft, Bettina F. Drake, and Alan Thompson

Subjects
Male, genetic association, genotype, Genome-wide association study, Bioinformatics, genetic risk, developed country, Prostate cancer, 0302 clinical medicine, Risk Factors, Genotype, Cooperative Behavior, breast cancer, cancer prognosis, cancer susceptibility, cell adhesion, cell cycle arrest, chromosome 14, chromosome 2, double stranded DNA break, embryo development, extracellular matrix, gene frequency, gene linkage disequilibrium, genetic predisposition, Gleason score, heterozygote, human, intron, priority journal, promoter region, prostate cancer, quality control, regulator gene, Oligonucleotide Array Sequence Analysis, 0303 health sciences, education.field_of_study, 3. Good health, 030220 oncology & carcinogenesis, Population, Single-nucleotide polymorphism, Biology, ta3111, Polymorphism, Single Nucleotide, 03 medical and health sciences, Meta-Analysis as Topic, Genetics, medicine, Humans, Genetic Predisposition to Disease, education, Genotyping, 030304 developmental biology, Case-control study, Cancer, Prostatic Neoplasms, medicine.disease, ta3122, Genetic Loci, Case-Control Studies, Genome-Wide Association Study
Abstract

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

Published
2016
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24. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author

Kenneth Offit, Hoda Anton-Culver, Ans M.W. van den Ouweland, Siranoush Manoukian, Christine L. Clarke, Kyriaki Michailidou, Antonis C. Antoniou, Maria Kabisch, Isabel dos-Santos-Silva, Douglas F. Easton, Curtis Olswold, Graham G. Giles, Tien Yin Wong, Ursula Eilber, Mads Thomassen, Christopher A. Haiman, Alice J. Sigurdson, Lothar Haeberle, Florence Menegaux, Ana Osorio, Marco Montagna, Katarzyna Jaworska-Bieniek, Eitan Friedman, Simon S. Cross, Daniel Barrowdale, Elinor J. Sawyer, Adam N. Freeman, Caroline Seynaeve, Min Hyuk Lee, Arnaud Droit, Per Hall, Minouk J. Schoemaker, Trinidad Caldés, Peter Hillemanns, Frederik Marmé, Jenny Lester, Michele M. Doody, Bernard Peissel, Peter Kraft, Elza Khusnutdinova, Anna H. Wu, Stéphanie Peeters, Georg Pfeiler, Pascal Guénel, Hidemi Ito, Xingyi Guo, Antoinette Hollestelle, Heli Nevanlinna, Kathleen Claes, Ylva Paulsson-Karlsson, Cecilia M. Dorfling, Roger L. Milne, Daehee Kang, Judith S. Brand, Diether Lambrechts, Olufunmilayo I. Olopade, Simona Agata, Saundra S. Buys, Muhammad Usman Rashid, Fabienne Lesueur, Alicia Beeghly-Fadiel, Peter Devilee, Manjeet K. Bolla, Natalia Antonenkova, Irene Konstantopoulou, Claudine Isaacs, Anja Rudolph, Carl Blomqvist, Tjoung Won Park-Simon, Judy Garber, Csilla Szabo, Francois Bacot, Arto Mannermaa, Yu-Tang Gao, Stig E. Bojesen, Susan L. Neuhausen, Marina Bermisheva, Qiuyin Cai, Zakaria Einbeigi, Christian F. Singer, Qin Wang, Kerstin Rhiem, Sofia Khan, Fiona Lalloo, Robert L. Nussbaum, Thilo Dörk, William J. Blot, Sylvie Mazoyer, Julia A. Knight, Katherine L. Nathanson, Clare Turnbull, Nazneen Rahman, Anne Lise Børresen-Dale, Chuen Neng Lee, Annegien Broeks, Martha J. Shrubsole, Ava Kwong, Jirong Long, Ian G. Campbell, Sara Margolin, Fergus J. Couch, Laima Tihomirova, Mary Beth Terry, Jenny Chang-Claude, Alice S. Whittemore, Joseph Vijai, Alfons Meindl, Xiao-Ou Shu, Shan Wang-Gohrke, Wei Zheng, Beth Y. Karlan, Jacques Simard, Angela Cox, Shahana Ahmed, Polly A. Newcomb, Ritu Salani, Chen-Yang Shen, Adalgeir Arason, Sandrine Tchatchou, Ute Hamann, Elizabeth J. van Rensburg, Michael Jones, Mark H. Greene, Anthony J. Swerdlow, Senno Verhoef, Jonine Figueroa, Hermann Brenner, Volker Arndt, Charles Joly Beauparlant, Esther M. John, Nadege Presneau, Jingmei Li, Laura Papi, Marjanka K. Schmidt, Montserrat Garcia-Closas, Uffe Birk Jensen, Georgia Chenevix-Trench, Paolo Peterlongo, Penny Soucy, Thomas Brüning, Jaana M. Hartikainen, Siddhartha Kar, Ji Yeob Choi, Manuel R. Teixeira, Phuong L. Mai, Alex Teulé, Jyh Cherng Yu, Paul Brennan, Maya Ghoussaini, Edith Olah, Henrik Flyger, Michael Friedlander, Soo Hwang Teo, Frans B. L. Hogervorst, Kathleen M. Egan, David J. Hunter, Kristiina Aittomäki, Joe Dennis, Anna González-Neira, Mikael Hartman, Alison M. Dunning, Doris Steinemann, Debra Frost, Melissa C. Southey, Ramunas Janavicius, Evgeny N. Imyanitov, Catherine M. Phelan, Amanda E. Toland, Anna Marie Mulligan, David ven den Berg, Rita K. Schmutzler, Julian Peto, Irene L. Andrulis, Chenjie Zeng, Kenneth Muir, Peter Schürmann, Saila Kauppila, Banu Arun, Jane Carpenter, Jeffrey N. Weitzel, Yael Laitman, Susan M. Domchek, Robert Winqvist, Caroline Baynes, Brita Arver, Marc Tischkowitz, Kamila Czene, Keitaro Matsuo, Barbara Burwinkel, Miriam Dwek, Kim De Leeneer, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Peter A. Fasching, Bernd Dworniczak, Susan J. Ramus, Lesley McGuffog, Andrea Gehrig, Michael J. Kerin, Thomas Hansen, Francesca Damiola, John L. Hopper, Loic Le Marchand, Peter J. Hulick, Annika Lindblom, Emily Hallberg, Miguel de la Hoya, Gaetana Gambino, Martine Dumont, Susan L. Slager, Bernardo Bonanni, Bent Ejlertsen, Norhashimah Hassan, Sue Healey, Orland Diez, Mary B. Daly, Carolyn B. Hendricks, Artitaya Lophatananon, Annelie Liljegren, Steven N. Hart, Jan Lubinski, Natalia Bogdanova, Drakoulis Yannoukakos, Steve Ellis, Silje Nord, Hiltrud Brauch, Gad Rennert, Conxi Lázaro, Daniel C. Tessier, Paolo Radice, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Suleeporn Sangrajrang, Karoline Kuchenbaecker, Javier Benitez, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, Medical Oncology, and Obstetrics & Gynecology

Subjects
0301 basic medicine, Fine-scale mapping, Genome-wide association study, HORMONE-RELATED PROTEIN, Epigenesis, Genetic, Breast cancer, Medizinische Fakultät, Databases, Genetic, Genotype, BRCA2 MUTATION CARRIERS, Odds Ratio, Medicine and Health Sciences, Pair 12, Medicine, Genetic risk factor, Promoter Regions, Genetic, Medicine(all), Genetics, BRCA1 Protein, PTHLH-CCDC91, Chromosome Mapping, LOCALIZATION, Single Nucleotide, PTHLH, 3. Good health, Enhancer Elements, Genetic, Population Surveillance, Female, Medical Genetics, BRAC1 mutation carriers, CCDC91, Alleles, Breast Neoplasms, Case-Control Studies, Computational Biology, European Continental Ancestry Group, Haplotypes, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study, Human, Research Article, EXPRESSION, Enhancer Elements, SUSCEPTIBILITY LOCI, 3122 Cancers, Single-nucleotide polymorphism, Chromosomes, White People, OVARIAN-CANCER, Càncer de mama, Promoter Regions, Databases, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic, Journal Article, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Genetic association, Cancer och onkologi, business.industry, Haplotype, Case-control study, Biology and Life Sciences, Odds ratio, medicine.disease, ENHANCERS, 030104 developmental biology, Cancer and Oncology, METASTASIS, 3111 Biomedicine, GENETIC MODIFIERS, business, Genètica, Epigenesis
Abstract

Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed

Published
2016
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25. CYP2D6 Gene Variants and Their Association with Breast Cancer Susceptibility

Author

Craig Luccarini, Allison M Dunning, Paul D.P. Pharoah, Helena M. Earl, Melanie Maranian, Bolot Kalmyrzaev, Radka Platte, Carlos Caldas, Caroline Baynes, Kristy Driver, and Jean Abraham

Subjects
Oncology, medicine.medical_specialty, Genotype, Epidemiology, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Bioinformatics, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, digestive system, Breast cancer, Risk Factors, Internal medicine, medicine, Humans, SNP, Genetic Predisposition to Disease, Breast, Rare functional variant, skin and connective tissue diseases, Case-control study, DNA, Neoplasm, Prognosis, medicine.disease, Minor allele frequency, Cytochrome P-450 CYP2D6, Case-Control Studies, Female, Tamoxifen, medicine.drug
Abstract

Background: The gene encoding the phase I enzyme cytochrome P4502D6 (CYP2D6) has been previously investigated for its potential predictive role in the efficacy of breast cancer treatments such as tamoxifen, but its role in breast cancer susceptibility is unclear. This study aims to evaluate the association between germ line variations in CYP2D6 and breast cancer susceptibility. Methods: DNA samples from 13,472 cases and controls were genotyped for seven known functional variants [minor allele frequency (MAF) ≥ 0.01] and five single nucleotide polymorphisms (SNP) that tag common genetic variation (MAF > 0.05) in CYP2D6. Results: One relatively rare functional variant, CYP2D6*6, (MAF = 0.01) showed a modest increased association with breast cancer susceptibility (Ptrend = 0.02; OR = 1.32; 95% CI = 1.04–1.68). All other functional and tagSNPs showed no association with breast cancer susceptibility. Conclusions: Common variants of CYP2D6 do not play a significant role in breast cancer susceptibility. However, this study raises questions regarding the role of rare variants, such as CYP2D6*6, in breast cancer susceptibility which merit further investigation. Impact: This large case–control study, involving 13,472 women, found no evidence of any association between common CYP2D6 gene variants and breast cancer susceptibility. However, one relatively rare functional variant CYP2D6*6 showed a modest association with breast cancer susceptibility, indicating that the role of rare CYP2D6 variants in breast cancer risk is unclear and requires further investigation in an adequately powered study. Cancer Epidemiol Biomarkers Prev; 20(6); 1255–8. ©2011 AACR.

Published
2011
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26. No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: Results from the RAPPER study

Author

Neil G. Burnet, Gillian C. Barnett, Paul D.P. Pharoah, Alison M. Dunning, Rebecca Elliott, Caroline Baynes, Catharine M L West, Charlotte E. Coles, and Jennifer S. Wilkinson

Subjects
Adult, Oncology, medicine.medical_specialty, Genotype, medicine.medical_treatment, Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Radiation Tolerance, Transforming Growth Factor beta1, Breast cancer, Fibrosis, Surveys and Questionnaires, Internal medicine, Biomarkers, Tumor, Photography, medicine, Humans, Radiology, Nuclear Medicine and imaging, Radiation Injuries, Aged, Aged, 80 and over, Chi-Square Distribution, Radiotherapy, business.industry, Incidence (epidemiology), Carcinoma, Ductal, Breast, Dose-Response Relationship, Radiation, Hematology, Middle Aged, medicine.disease, Radiation therapy, Logistic Models, Toxicity, Immunology, Female, business, Genome-Wide Association Study
Abstract

Several small studies have reported associations between TGFB1 single nucleotide polymorphisms (SNPs), considered to increase secretion of TGF-β1, and greater than 3-fold increases in incidence of fibrosis - an indicator of late toxicity after radiotherapy in breast cancer patients.Two SNPs in TGFB1, C-509T (rs1800469) and L10P (rs1800470), were genotyped in 778 breast cancer patients who had received radiotherapy to the breast. Late radiotherapy toxicity was assessed two years after radiotherapy using a validated photographic technique, clinical assessment and patient questionnaires.On photographic assessment, 210 (27%) patients showed some degree of breast shrinkage, whilst 45 (6%) patients showed marked breast shrinkage. There was no significant association of genotype at either of the TGFB1 SNPs with any measure of late radiation toxicity.This adequately powered trial failed to confirm previously reported increases in fibrosis with TGFB1 genotype - any increase greater than 1.36 can be excluded with 95% confidence. Similar frequent failures to replicate associations with candidate genes have been resolved using genome-wide association scans: this methodology detects common, low risk alleles but requires even larger patient numbers for adequate statistical power.

Published
2010
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27. Common Single-Nucleotide Polymorphisms in DNA Double-Strand Break Repair Genes and Breast Cancer Risk

Author

Elizabeth M. Azzato, Paul D.P. Pharoah, Bruce A.J. Ponder, Douglas F. Easton, Alison M. Dunning, Jonathan Tyrer, Karen A. Pooley, Kristy Driver, and Caroline Baynes

Subjects
Adult, DNA Repair, Genotype, Epidemiology, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, XRCC2, Breast cancer, medicine, Humans, Genetic Predisposition to Disease, Allele, Alleles, Aged, Proportional Hazards Models, Genetics, Chi-Square Distribution, Hazard ratio, Cancer, Odds ratio, Middle Aged, Prognosis, medicine.disease, DNA-Binding Proteins, Minor allele frequency, Haplotypes, Oncology, Case-Control Studies, Female, Receptors, Progesterone
Abstract

The proteins involved in homologous recombination are instrumental in the error-free repair of dsDNA breakages, and common germ-line variations in these genes are, therefore, potential candidates for involvement in breast cancer development and progression. We carried out a search for common, low-penetrance susceptibility alleles by tagging the common variation in 13 genes in this pathway in a two-stage case-control study. We genotyped 100 single-nucleotide polymorphisms (SNP), tagging the 655 common SNPs in these genes, in up to 4,470 cases and 4,560 controls from the SEARCH study. None of these tagging SNPs was associated with breast cancer risk, with the exception of XRCC2 rs3218536, R188H, which showed some evidence of a protective association for the rare allele [per allele odds ratio, 0.89; 95% confidence intervals (95% CI), 0.80-0.99; P trend = 0.03]. Further analyses showed that this effect was confined to a risk of progesterone receptor positive tumors (per rare allele odds ratio, 0.78; 95% CI, 0.66-0.91; P trend = 0.002). Several other SNPs also showed receptor status-specific susceptibility and evidence of roles in long-term survival, with the rare allele of BRIP1 rs2191249 showing evidence of association with a poorer prognosis (hazard ratio per minor allele, 1.20; 95% CI, 1.07-1.36; P trend = 0.002). In summary, there was little evidence of breast cancer susceptibility with any of the SNPs studied, but larger studies would be needed to confirm subgroup effects. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3482–9)

Published
2008
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28. Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Author

Martine Tranchant, Fergus J. Couch, Meeri Otsukka, Sabine Behrens, Jirong Long, Nadia Obi, Kamila Czene, John L. Hopper, Heather Thorne, Robert Pilarski, Anja Rudolph, Simon S. Cross, Volker Harth, Gabrielle Colleran, Hatef Darabi, Thomas Van Brussel, Eunjung Lee, Anne Lotz, E. Krol-Warmerdam, M. Pilar Zamora, Qin Wang, Andy C. H. Lee, Annie Fung, Kara Sargus, Melissa C. Southey, Katja Butterbach, Nuria Álvarez, Francois Bacot, Jeffrey G. Meyer, Ian W. Brock, Jessica Clague De Hart, Pierre Laurent-Puig, Irene L. Andrulis, Pei Chao, Arnaud Droit, Per Hall, Daniel C. Tessier, Paolo Radice, Frederic Robidoux, Don M. Conroy, Irja Erkkilä, Daniel Vincent, Antoinette Hollestelle, Christopher A. Hilker, Alicia Beeghly-Fadiel, Muhabbet Celik, Peggy Reynolds, Caroline Baynes, Sophia S. Wang, Katri Pylkäs, Kang In Nee, Robert Winqvist, Henrik Flyger, Annette Heemskerk, Sara Margolin, Hui Cai, Julie M. Cunningham, Prat Boonyawongviroj, Bernardo Bonanni, Anthony J. Swerdlow, Dan Connley, Huiyan Ma, Valerie Gaborieau, David O. Nelson, Keitaro Matsuo, Sylvie La Boissière, Pornthep Siriwanarungsan, Hidemi Ito, Ursula Eilber, Matthias W. Beckmann, Sylvia Rabstein, Natalia Bogdanova, Anna Jakubowska, Yves Raoul, Robert A.E.M. Tollenaar, Frans B. L. Hogervorst, Hannah L Park, Pierre Kerbrat, Ying Zheng, Paul D.P. Pharoah, Wanqing Wen, Judith Heinz, Annika Lindblom, Christa Stegmaier, Manjeet K. Bolla, Loris Bernard, Anna H. Wu, Alison M. Dunning, Hermann Brenner, A. Green, Thilo Dörk, Chia-Ni Hsiung, Dennis Deapen, Michael G. Schrauder, Gilian Peuteman, S.E. Higham, Sabapathy P. Balasubramanian, Irene Feroce, Christina Justenhoven, Angela Jones, William J. Blot, Nichola Johnson, Petra Seibold, D. Bowtell, Jiajun Shi, Wei Zheng, U Hamann, Pascal Guenel, P. Webb, Soo Hwang Teo, Daniela Zaffaroni, J. Blom, Rita K. Schmutzler, Douglas F. Easton, Yani Lu, Witold Zatonski, Phuah Sze Yee, Susan L. Neuhausen, Kenneth Muir, Sofia Khan, Daehee Kang, Silke Landrith, Helena Kemiläinen, Maggie Angelakos, Rich Pinder, Javier Benitez, Til Olchers, Senno Verhoef, Fred Schumacher, Martha J. Shrubsole, Teresa Selander, Teh Yew Ching, Christof Sohn, Patrick Arveux, Dorota M. Gertig, Saila Kauppila, Mervi Grip, Florentia Fostira, Jenny Chang-Claude, Michael Stagner, Kathleen Corthouts, Ellen Van Der Schoot, H Nevanlinna, Peter Bugert, Christian Baisch, Eija Myöhänen, Sonja Wolf, Hoda Anton-Culver, Nicola Miller, Cheng Har Yip, Neonila Szeszenia-Dabrowska, Nicholas K. Hayward, Dieter Flesch-Janys, Barbara Burwinkel, J. Molenaar, Eileen Williams, Marjanka K. Schmidt, Yon Ko, Anja Nieuwlaat, Chen-Yang Shen, Veli-Matti Kosma, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Artitaya Lophatananon, Mikael Hartman, Jonathan Beesley, Bernard Peissel, Paolo Peterlongo, Ji Yeob Choi, Craig Luccarini, Rosalind A. Eeles, Niall M. McInerney, Bernard Thienpont, Xiao-Ou Shu, Léa Héguy, Maya Ghoussaini, Sander Canisius, Wing-Yee Lo, Suleeporn Sangrajrang, Nur Aishah Taib, June Yashiki, Kirsimari Aaltonen, Louise A. Brinton, Elinor J. Sawyer, Alina Vrieling, Angela Cox, Frederik Marmé, Matthias Rübner, Graham G. Giles, Sonja Oeser, Hans Christiansen, Andrew Rowan, Ed Dicks, Andeas Schneeweiß, Catriona McLean, Antonis C. Antoniou, B. Pesch, Eveline Niedermayr, Volker Arndt, Janet E. Olson, Dominiek Smeets, Jingmei Li, Georgia Chenevix-Trench, Claire Mulot, Siranoush Manoukian, Hans Fischer, Ellen Crepin, Arto Mannermaa, Ali Amin Al Olama, Helen Cramp, Ans M.W. van den Ouweland, Olivia Fletcher, Sharon A. Windebank, Peter Hillemanns, Nayana Weerasooriya, James V. Lacey, Leslie Bernstein, Romuald Le Scodan, Giulietta Scuvera, P. Parsons, Thomas C. Putti, Elaine Ryder-Mills, Sara Benlloch, Beata Peplonska, Stig E. Bojesen, Kimberley Chua, Stefan Nickels, Nick Orr, Roger L. Milne, Tuomas Heikkinen, Christopher A. Haiman, Natalia Antonenkova, Volker Hermann, Maria Kabisch, Kenneth Offit, Julia A. Knight, Angela Maniscalco, Arja Jukkola-Vuorinen, Hartwig Ziegler, Chenjie Zeng, Jacques Simard, Pamela L. Horn-Ross, Daphne S.C. Lee, Xingyi Guo, Jan Lubinski, Michael J. Kerin, Loic Le Marchand, Sune F. Nielsen, Peter Devilee, A. De Fazio, Qiuyin Cai, Annie Turgeon, Yoon Sook-Yee, Silje Nord, Petra Bos, Hiltrud Brauch, Kyriaki Michailidou, Shivaani Mariapun, Kari Mononen, Alfons Meindl, Peter B. Kang, Siddhartha Kar, Alessandra Rossi, G. Chenevix-Trench, Diether Lambrechts, Karl von Smitten, Zsofia Kote-Jarai, Emiel J. Th. Rutgers, Chiu-Chen Tseng, Peter A. Fasching, Lesley McGuffog, Annegien Broekss, Johann H. Karstens, Montserrat Garcia-Closas, Thomas Brüning, David C. Whiteman, Judi Maskiell, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, and Obstetrics & Gynecology

Subjects
Genetic Markers, Linkage disequilibrium, Epidemiology, Locus (genetics), Genome-wide association study, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics, Molecular epidemiology, Case-control study, Chromosome Mapping, medicine.disease, Logistic Models, Oncology, Genetic marker, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 4, Genome-Wide Association Study
Abstract

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

Published
2015

29. Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

Author

S. Lindstrom, Javier Benitez, Natalia Bogdanova, Christine B. Ambrosone, Judith S. Brand, Joe Dennis, Hoda Anton-Culver, Carl Blomqvist, Katarzyna Durda, Loic Le Marchand, Hiltrud Brauch, Aida Karina Dieffenbach, Veli-Matti Kosma, Heli Nevanlinna, Caroline Seynaeve, Drakoulis Yannoukakos, Gord Glendon, Stephen Burgess, Kyriaki Michailidou, Jolanta Lissowska, Thilo Dörk, Paolo Peterlongo, Helen Tsimiklis, J Lubinski, Melissa C. Southey, Robert Winqvist, Kamila Czene, Sune F. Nielsen, Anja Rudolph, Vessela N. Kristensen, Alison M. Dunning, Catherine S. Healey, Diether Lambrechts, Christi J. van Asperen, M. Rosario Alonso, C. Stegmaier, Giuseppe Floris, Per Hall, Jaana M. Hartikainen, Chun Li, Malcolm W.R. Reed, Nuria Álvarez, Anna Jakubowska, Paul D.P. Pharoah, Sara Margolin, John L. Hopper, Barbara Perkins, Francois Bacot, Michael Jones, Jacques Simard, Katarzyna Jaworska-Bieniek, Fredrick R. Schumacher, Angela Cox, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, Arja Jukkola-Vuorinen, Arif B. Ekici, Mervi Grip, Rongxi Yang, Esther M. John, Kathleen E. Malone, Vesa Kataja, Qin Wang, Fergus J. Couch, Keith Humphreys, Katja van den Hurk, Michael J. Kerin, Anna González-Neira, Jenny Chang-Claude, Daniel Vincent, Wei Zheng, Ian Tomlinson, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Amanda E. Toland, Xiao-Ou Shu, Dieter Flesch-Janys, Volker Arndt, Graham G. Giles, Rita K. Schmutzler, Julian Peto, Craig Luccarini, Børge G. Nordestgaard, Grethe I. Grenaker Alnæs, Alice S. Whittemore, Olivia Fletcher, Guillermo Pita, Matti A. Rookus, Barbara Burwinkel, Lothar Haeberle, Hermann Brenner, John W. M. Martens, Mitul Shah, Marilie D. Gammon, Patrick Neven, Emilie Cordina-Duverger, Jose Ignacio Arias Perez, Ben Zhang, Martine Dumont, Mel Maranian, Annika Lindblom, Habibul Ahsan, Susan L. Neuhausen, Mikael Eriksson, Jingmei Li, Carmel Apicella, Frederik Marmé, Peter Kraft, Hatef Darabi, Ulrike Peters, Hans Wildiers, Arto Mannermaa, J. Margriet Collée, Pascal Guénel, Peter Devilee, M.J. Hooning, Daniel C. Tessier, Shahana Ahmed, Paolo Radice, Montserrat Garcia-Closas, Elinor J. Sawyer, Louise A. Brinton, Susan L. Slager, Bernardo Bonanni, Peter A. Fasching, Simon S. Cross, Thérèse Truong, Matthias W. Beckmann, Catriona McLean, Douglas F. Easton, Georgia Chenevix-Trench, David J. Hunter, Kristiina Aittomäki, Janet E. Olson, Henrik Flyger, Chenjie Zeng, Nick Orr, Siranoush Manoukian, Antonenkova Nn, Stig E. Bojesen, Wan-Qing Wen, Jirong Long, Nicola Miller, Brandon L. Pierce, Ryan J. Delahanty, Anthony J. Swerdlow, Brian E. Henderson, Harald Surowy, Yon-Dschun Ko, Celine M. Vachon, Daniel Herrero, Christopher A. Haiman, Sandrine Tchatchou, Florence Menegaux, Katri Pylkäs, Taru A. Muranen, Roger L. Milne, Thomas Brüning, Marjanka K. Schmidt, Manjeet K. Bolla, M. Pilar Zamora, Irene L. Andrulis, Caroline Baynes, Emily Hallberg, D. Seminara, Isabel dos-Santos-Silva, Diana Torres, Wim L. A. M. de Kort, Nichola Johnson, Public and occupational health, Clinical Genetics, Virology, Medical Oncology, Surgery, and Landsteiner Laboratory

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, coronary-artery-disease, prospective cohort, Genome-wide association study, Breast Neoplasms, Article, different anatomic sites, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, Internal medicine, common variants, Mendelian randomization, Odds Ratio, Medicine, Humans, Prospective Studies, Risk factor, Prospective cohort study, Evidence-Based Medicine, business.industry, body-fat distribution, Mendelian Randomization Analysis, multiple genetic-variants, Odds ratio, medicine.disease, susceptibility loci, Body Height, interleukin-6 receptor, adult human height, Relative risk, genome-wide association, Female, business
Abstract

Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5 216 302 women, including 113 178 events. In a consortium with individual-level data from 46 325 case patients and 42 482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16 003 case patients and 41 335 control subjects. Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10 cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10 cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5 × 10-8. Conclusions: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.

Published
2015
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30. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer

Author

Melissa C. Southey, Fredrick R. Schumacher, Robert Winqvist, Simon S. Cross, Katarzyna Durda, Anna Jakubowska, Paul D.P. Pharoah, Judith S. Brand, Christi J. van Asperen, Javier Benitez, Isabel dos-Santos-Silva, Douglas F. Easton, Roger L. Milne, Justo Lorenzo Bermejo, Hermann Brenner, Patrick Neven, Frederik Marmé, Marie Sanchez, Peter Bugert, Maria Kabisch, Anja Rudolph, Arto Mannermaa, Thilo Dörk, Diether Lambrechts, Anna González-Neira, Hoda Anton-Culver, Thomas Dünnebier, Matthias Ruebner, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Veli-Matti Kosma, Christopher A. Haiman, Dieter Flesch-Janys, Martha J. Shrubsole, Florence Menegaux, Catriona McLean, Olivia Fletcher, Kamila Czene, Mark S. Goldberg, Per Hall, Jacques Simard, Keith Humphreys, Qin Wang, Georgia Chenevix-Trench, Katarzyna Jaworska-Bieniek, Jan Lubinski, Loic Le Marchand, Katri Pylkäs, Barbara Perkins, Kristen S. Purrington, Daniel C. Tessier, Paolo Radice, Craig Luccarini, Sune F. Nielsen, Paolo Peterlongo, Nicola Miller, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, John L. Hopper, Annegien Broeks, Kristiina Aittomäki, Mieke Kriege, Sandrine Tchatchou, Frans B. L. Hogervorst, Jenny Chang-Claude, Robert A.E.M. Tollenaar, Angela Cox, Maartje J. Hooning, Brian E. Henderson, Seth W. Slettedahl, Montserrat Garcia-Closas, Thomas Brüning, Malcolm W.R. Reed, Francois Bacot, Alison M. Dunning, kConFab Investigators, Julian Peto, Børge G. Nordestgaard, Linetta B. Koppert, Volker Arndt, Rongxi Yang, Celine M. Vachon, Peter Devilee, Qiuyin Cai, Caroline Weltens, Hiltrud Brauch, Heli Nevanlinna, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Stig E. Bojesen, Giulietta Scuvera, Kyriaki Michailidou, Jolanta Lissowska, Marjanka K. Schmidt, Fergus J. Couch, Barbara Burwinkel, Ute Hamann, Jaana M. Hartikainen, Janet E. Olson, Natalia Bogdanova, Irene L. Andrulis, M. Pilar Zamora, Caroline Baynes, Gord Glendon, Wei Zheng, Taru A. Muranen, Drakoulis Yannoukakos, Caroline Seynaeve, Aida Karina Dieffenbach, Stefano Fortuzzi, Mel Maranian, Arif B. Ekici, Nick Orr, Annika Lindblom, Nichola Johnson, Arja Jukkola-Vuorinen, Anthony J. Swerdlow, Peter A. Fasching, Sten Cornelissen, Martine Dumont, Diana Torres, Helen Tsimiklis, Yon-Dschun Ko, Vesa Kataja, Shibo Ying, Jingmei Li, Carmel Apicella, Vessela N. Kristensen, Hatef Darabi, Christa Stegmaier, Stéphanie Peeters, Michael J. Kerin, Graham G. Giles, Elinor J. Sawyer, Minouk J. Schoemaker, Manjeet K. Bolla, Carl Blomqvist, Xianshu Wang, Joe Dennis, Stephen J. Chanock, Mervi Grip, Jose Ignacio Arias Perez, Mikael Eriksson, Daniel Vincent, Antoinette Hollestelle, Pascal Guénel, Shahana Ahmed, Henrik Flyger, Clinical Genetics, Medical Oncology, and Surgery

Subjects
Risk, Cancer Research, Candidate gene, kinase, Chromosomal Proteins, Non-Histone, Survivin, European Continental Ancestry Group, Estrogen receptor, cytokinesis, Original Manuscript, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, Cell Cycle Proteins, Biology, metaphase, Polymorphism, Single Nucleotide, White People, Inhibitor of Apoptosis Proteins, Breast cancer, SDG 3 - Good Health and Well-being, Medizinische Fakultät, cleavage furrow, Genotype, medicine, Aurora Kinase B, Humans, Genetic Predisposition to Disease, ddc:610, Allele, skin and connective tissue diseases, 3' Untranslated Regions, mitosis, Genetics, INCENP, aurora-b, General Medicine, medicine.disease, segregation, mammaglobin, Receptors, Estrogen, midbody, Case-Control Studies, Female, Genome-Wide Association Study
Abstract

The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixedeffects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007 and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated. © The Author 2015.

Published
2015

31. Poster group 6 – Other genes and molecules involved in the immune response

Author

W. Martin Howell, Alison M. Dunning, Bruce Ponder, Caroline Baynes, Philip R. Evans, Roz Gibbs, Elizabeth A. Bulpitt, and Douglas F. Easton

Subjects
business.industry, Immunology, Single-nucleotide polymorphism, medicine.disease, Vascular endothelial growth factor, chemistry.chemical_compound, Interleukin 10, Breast cancer, chemistry, Genetics, Cancer research, Medicine, business, Genetics (clinical)
Published
2004
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32. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author

Suleeporn Sangrajrang, James McKay, Jirong Long, Gord Glendon, Qi Guo, Malcolm W.R. Reed, Yon Dschun Koto, Sara Margolin, Francois Bacot, Julian Peto, Shaik Ahmad Buhari, Fredrick R. Schumacher, Jose Ignacio Arias Perez, Børge G. Nordestgaard, Kamila Czene, Barbara Burwinkel, Mikael Eriksson, Lorna Gibson, Mitul Shah, Matthias W. Beckmann, Shahana Ahmed, Anthony J. Swerdlow, Frederik Marmé, Pascal Guénel, Hidemi Ito, Mark S. Goldberg, Laura J. van't Veer, John W.M. Martens, Wei Zheng, John L. Hopper, Susanne Kaufmann, Carlos Caldas, Jonathan Beesley, Paolo Peterlongo, Ji Yeob Choi, Daniel O. Stram, Sarah Stewart-Brown, Elinor J. Sawyer, Craig Luccarini, Anja Rudolph, Qin Wang, Javier Benitez, Marie Sanchez, Daniel Herrero, Catherine S. Healey, Arto Mannermaa, Daniel C. Tessier, Paolo Radice, David Van Den Berg, Jacques Simard, Hoda Anton-Culver, Stephen J. Chanock, Christopher A. Haiman, Ines de Santiago, Minouk J. Schoemaker, Irene L. Andrulis, Veli-Matti Kosma, Isabel dos-Santos-Silva, Caroline Baynes, Douglas F. Easton, Stacey L. Edwards, Florence Menegaux, Hatef Darabi, Kyriaki Michailidou, Anna H. Wu, Carolien H.M. van Deurzen, Annegien Broeks, Paul Brennan, Sonja Helbig, Melissa C. Southey, Daniel Klevebring, Loic Le Marchand, Katri Pylkäs, J. Margriet Collée, Ed Dicks, Robert A.E.M. Tollenaar, Henrik Flyger, Jenny Chang-Claude, Annika Lindblom, Christine B. Ambrosone, Lothar Haeberle, Janet E. Olson, Sune F. Nielsen, Robert Winqvist, M. Pilar Zamora, Emily Hallberg, Vessela N. Kristensen, Hermann Brenner, Diana Torres, Valerie Gaborieau, Keitaro Matsuo, Yu-Tang Gao, Yik Ying Teo, Anna Jakubowska, Paul D.P. Pharoah, Patrick Neven, Vesa Kataja, Fergus J. Couch, Robert Luben, Ute Hamann, Katarzyna Jaworska-Bieniek, Dylan M. Glubb, Nick Orr, Christi J. van Asperen, Sara Volorio, Tien Yin Wong, Keith Humphreys, Jianjun Liu, Helen Tsimiklis, Thilo Dörk, Jaana M. Hartikainen, Guillermo Pita, Daniel Vincent, Roger L. Milne, M. Rosario Alonso, Nuria Álvarez, Chiu-Chen Tseng, Daehee Kang, Martine Dumont, Richard Cowper-Sal-lari, Mathieu Lupien, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Xiao-Ou Shu, Brian E. Henderson, Miroslav Kapuscinski, Hui Miao, Angela Cox, Caroline Seynaeve, Stig E. Bojesen, Jason S. Carroll, Nicola Miller, Marjanka K. Schmidt, Taru A. Muranen, Celine M. Vachon, Manjeet K. Bolla, Hans Wildiers, Carl Blomqvist, Maartje J. Hooning, Sandrine Tchatchou, Maya Ghoussaini, Cheng Har Yip, Artitaya Lophatananon, Graham G. Giles, Penny Webb, Yasushi Yatabe, Aida Karina Dieffenbach, Mikael Hartman, Volker Arndt, Simon S. Cross, Per Hall, Soo Hwang Teo, Arif B. Ekici, Joe Dennis, Heli Nevanlinna, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Jolanta Lissowska, Kinjal Desai, Alan Ashworth, Jan Lubinski, Primitiva Menéndez, Pei Ei Wu, Natalia Bogdanova, Kristine M. Hillman, Juliet D. French, Andreas Schneeweiss, Drakoulis Yannoukakos, Montserrat Garcia-Closas, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Thomas Brüning, Kristiina Aittomäki, Silje Nord, Jyh Cherng Yu, Hiltrud Brauch, Peter Devilee, Anne Lise Børresen-Dale, Susan L. Slager, Melissa A. Brown, Qiuyin Cai, Hiroji Iwata, Diether Lambrechts, Bernardo Bonanni, Katarzyna Durda, Emiel J. Th. Rutgers, Grethe I. Grenaker Alnæs, Anna de Fazio, Siddhartha Kar, Mel Maranian, Susan L. Neuhausen, Judith E. Brown, Christof Sohn, Sue K. Park, Christa Stegmaier, Shou Tung Chen, Dong-Young Noh, Bernard Thienpont, Alison M. Dunning, Kenneth Muir, Daphne S.C. Lee, Michael J. Kerin, Dieter Flesch-Janys, Jingmei Li, Chen-Yang Shen, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Pathology, Cardiothoracic Surgery, International Institute of Social Studies, Ghoussaini, Maya [0000-0002-2415-2143], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dicks, Ed [0000-0002-0617-0401], Luben, Robert [0000-0002-5088-6343], Carroll, Jason [0000-0003-3643-0080], Caldas, Carlos [0000-0003-3547-1489], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
General Physics and Astronomy, Genome-wide association study, in-vivo, Genotype, phase, cyclin d1 expression, Promoter Regions, Genetic, CYCLIN D1 EXPRESSION, IN-VIVO, Genetics, Multidisciplinary, FACTOR-BINDING PROTEIN-5, foxa1, ASSOCIATION, Chromatin, 3. Good health, Multidisciplinary Sciences, Chromosomes, Human, Pair 2, functional variants, MCF-7 Cells, Science & Technology - Other Topics, GROWTH, Female, Hepatocyte Nuclear Factor 3-alpha, growth, PHASE, Breast Neoplasms, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Breast cancer, SDG 3 - Good Health and Well-being, Cell Line, Tumor, medicine, Humans, SNP, Genetic Predisposition to Disease, RNA, Messenger, FUNCTIONAL VARIANTS, Gene, Science & Technology, association, Correction, General Chemistry, medicine.disease, CELLS, factor-binding protein-5, cells, FOXA1, Insulin-Like Growth Factor Binding Protein 5
Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology. ispartof: Nature communications vol:5 pages:4999- ispartof: location:England status: published

Published
2014

33. Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

Author

Yu Tang Gao, Senno Verhoef, Sofia Khan, Brian E. Henderson, M. Pilar Zamora, Roger L. Milne, Qin Wang, Jaana M. Hartikainen, Joshua A. Betts, Montserrat Garcia-Closas, Gianluca Severi, Shahana Ahmed, Katarzyna Durda, Pascal Guénel, Hidemi Ito, Manjeet K. Bolla, Francois Bacot, Gord Glendon, Hermann Brenner, Chen-Yang Shen, Suleeporn Sangrajrang, James McKay, Fergus J. Couch, Nicholas W. Knoblauch, Vernon S. Pankratz, Dieter Flesch-Janys, Henrik Flyger, Pierre Laurent-Puig, Isabel dos Santos Silva, Heiko Müller, Nichola Johnson, Alfons Meindl, Nicola Miller, Christian R. Loehberg, Mark S. Goldberg, Mikael Hartman, Daniel C. Tessier, Paolo Radice, Ann Smeets, Ute Hamann, Xueling Sim, Irene L. Andrulis, Caroline Baynes, Annika Lindblom, Craig Luccarini, Laura Baglietto, Kristiina Aittomäki, Nils Schoof, Ana-Teresa Maia, Andrew K. Godwin, David Van Den Berg, Katri Pylkäs, Caroline M. Seynaeve, Madeleine M.A. Tilanus-Linthorst, Chiu-Chen Tseng, Angela Cox, Jirong Long, Stacey L. Edwards, Kerstin B. Meyer, Daniel R. Barnes, Per Hall, Melissa C. Southey, Wei Zheng, Stig E. Bojesen, Maartje J. Hooning, Daniel Herrero, William Blot, Don M. Conroy, Alison M. Dunning, John W.M. Martens, Artitaya Lophatananon, Christopher A. Haiman, Frederik Marmé, Sabapathy P. Balasubramanian, Florence Menegaux, Peter Kraft, Sarah Stewart-Brown, Julian Peto, Volker Arndt, Kenneth Muir, Daniel Klevebring, Robert Winqvist, Jose Ignacio Arias Perez, Joe Dennis, Sune F. Nielsen, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Valerie Gaborieau, Børge G. Nordestgaard, Anthony J. Swerdlow, Mitul Shah, M. Rosario Alonso, Keitaro Matsuo, Daniel O. Stram, Hui Cai, Anja Rudolph, Arto Mannermaa, Hiroji Iwata, Matthias W. Beckmann, Eranga N. Vithana, Elinor J. Sawyer, Anna Jakubowska, Paul D.P. Pharoah, Barbara Burwinkel, Annegien Broeks, Julia A. Knight, Alan Ashworth, Diether Lambrechts, Zoe Aitken, Marjanka K. Schmidt, Peter Bailey, Catherine S. Healey, Chia-Ni Hsiung, Anna González-Neira, Lisa B. Signorello, Thilo Dörk, Keun-Young Yoo, Maya Ghoussaini, J. H. Sng, J. Margriet Collée, Sten Cornelissen, Aiko Sueta, Melissa A. Brown, Nick Orr, Peter Lichtner, Hiltrud Brauch, Douglas F. Easton, Jonine D. Figueroa, Anna H. Wu, Kristine M. Hillman, Domenico Sardella, Dong Young Noh, Minouk J. Schoemaker, Fredrick R. Schumacher, Martine Dumont, Jianjun Liu, Kyriaki Michailidou, Stephen J. Chanock, Rita K. Schmutzler, Vesa Kataja, Kamila Czene, Natalia Antonenkova, Mervi Grip, Heli Nevanlinna, Georgia Chenevix-Trench, Peter Devilee, Qiuyin Cai, Pornthep Siriwanarangsan, Jolanta Lissowska, Christine B. Ambrosone, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Jenny Chang-Claude, Kirsimari Aaltonen, John L. Hopper, Bruce A.J. Ponder, Giuseppe Floris, Christa Stegmaier, Xianshu Wang, Cheng Har Yip, Christina Justenhoven, Vessela N. Kristensen, Jingmei Li, Shou Tung Chen, Karen A. Pooley, Jonathan Tyrer, Bernardo Bonanni, Sara Margolin, Päivi Heikkilä, Keith Humphreys, Martin O'Reilly, Sandra Deming-Halverson, Thomas L. Carroll, Pei Ei Wu, Soo Hwang Teo, Hui Miao, Stéphanie Peeters, Christof Sohn, Constance Chen, Jacques Simard, Jan Lubinski, Daehee Kang, Natalia Bogdanova, Juliet D. French, Christoph Engel, Adam M. Lee, Katarzyna Jaworska-Bieniek, Drakoulis Yannoukakos, Andreas Schneeweiss, Mel Maranian, Michael J. Kerin, Loic Le Marchand, Martha J. Shrubsole, Carl Blomqvist, Char Hong Ng, Daniel Vincent, Jonathan Beesley, Paolo Peterlongo, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Ed Dicks, Arif B. Ekici, Andrew H. Beck, Xiao-Ou Shu, Graham G. Giles, Stefan Nickels, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Surgery, and Cardiothoracic Surgery

Subjects
Messenger, Electrophoretic Mobility Shift Assay, Enhancer RNAs, Genome-wide association study, Medical and Health Sciences, prostate-cancer, 0302 clinical medicine, 2.1 Biological and endogenous factors, Genetics(clinical), Cyclin D1, Aetiology, RNA, Small Interfering, Pair 11, Promoter Regions, Genetic, Luciferases, Genetics (clinical), Cancer, estrogen-receptor, Genetics & Heredity, Genetics, Regulation of gene expression, 0303 health sciences, Tumor, Silencer Elements, Reverse Transcriptase Polymerase Chain Reaction, Single Nucleotide, Biological Sciences, Chromatin, Gene Expression Regulation, Neoplastic, Enhancer Elements, Genetic, 030220 oncology & carcinogenesis, kConFab Investigators, Female, Transcriptional, GENICA Network, Human, Chromatin Immunoprecipitation, Enhancer Elements, Breast Neoplasms, GATA3 Transcription Factor, Biology, Small Interfering, Real-Time Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, Chromosomes, Cell Line, multiple loci, Promoter Regions, 03 medical and health sciences, down-regulation, Genetic, SDG 3 - Good Health and Well-being, Cell Line, Tumor, Binding Sites, Case-Control Studies, Chromosomes, Human, Pair 11, Humans, RNA, Messenger, Silencer Elements, Transcriptional, ets-Domain Protein Elk-4, Breast Cancer, Polymorphism, Enhancer, Transcription factor, 030304 developmental biology, Neoplastic, gene-expression, susceptibility loci, growth-factor receptor-2, cell-cycle, Gene Expression Regulation, genome-wide association, Cancer research, RNA, mammary-gland, Chromatin immunoprecipitation
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. © 2013 The American Society of Human Genetics.

Published
2013

34. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Author

Don M. Conroy, David E. Neal, Jong Y. Park, Johanna Schleutker, Gerald L. Andriole, Amanda B. Spurdle, Peter Kraft, Alison M. Dunning, Esther M. John, Angela Morgan, Kenneth Muir, Douglas F. Easton, Fredrick R. Schumacher, Susan M. Gapstur, Rosalind A. Eeles, Stig E. Bojesen, Zsofia Kote-Jarai, Paul D.P. Pharoah, Francois Bacot, Jan Lubinski, Janet L. Stanford, Hermann Brenner, Cezary Cybulski, Caroline Baynes, Judith A. Clements, Jenny L Donovan, Ruth C. Travis, Edward J. Saunders, Kay-Tee Khaw, Silvia Halim, Demetrius Albanes, Stephen J. Chanock, Malgorzata Tymrakiewicz, Manuel R. Teixeira, D J Schaid, Sara Lindström, Loic Le Marchand, Sarah Jugurn-Little, Stephen N. Thibodeau, Fredrik Wiklund, Lisa A. Cannon-Albright, Maren Weischer, David J. Hunter, Graham G. Giles, Brian E. Henderson, Rosemary A. Wilkinson, Lisa B. Signorello, Michelle Guy, Craig Luccarini, Daniel Leongamornlert, Elio Riboli, Henrik Grönberg, Timothy J. Key, Christiane Maier, Joe Dennis, Walther Vogel, Ali Amin Al Olama, Helen Ross-Adams, Sonja I. Berndt, Ed Dicks, Sara Benlloch, Daniel Vincent, Freddie C. Hamdy, Sue A. Ingles, D. Campa, Rudolf Kaaks, Adam S. Kibel, Gianluca Severi, Daniel C. Tessier, Tokhir Dadaev, Christopher A. Haiman, Richard B. Hayes, Radka Kaneva, Koveela Govindasami, Emma J. Sawyer, Jyotsna Batra, Roslin Russel, Elaine A. Ostrander, and Federico Canzian

Subjects
Male, Linkage disequilibrium, genetic association, cancer risk, urologic and male genital diseases, Bioinformatics, Linkage Disequilibrium, Prostate cancer, 0302 clinical medicine, single nucleotide polymorphism, chromosome 5p, Genotype, genetic variability, Promoter Regions, Genetic, Telomerase, Genetics (clinical), Genetics, Prostate cancer risk, 0303 health sciences, gene, gene expression, gene locus, gene mapping, human, human tissue, priority journal, prostate cancer, TERT gene, 030302 biochemistry & molecular biology, Chromosome Mapping, General Medicine, 030220 oncology & carcinogenesis, HMG-CoA reductase, Chromosomes, Human, Pair 5, Corrigendum, Adult, medicine.medical_specialty, Single-nucleotide polymorphism, Computational biology, Biology, ta3111, Polymorphism, Single Nucleotide, RC0254, 03 medical and health sciences, Molecular genetics, Genetic variation, medicine, Humans, Telomerase reverse transcriptase, Genetic Predisposition to Disease, Genotyping, QH426, Molecular Biology, 030304 developmental biology, Prostatic Neoplasms, medicine.disease, ta3122, Case-Control Studies, biology.protein, Imputation (genetics)
Abstract

Associations between single nucleotide polymorphisms (snps) at 5p15 and multiple cancer types have been reported. we have previously shown evidence for a strong association between prostate cancer (prca) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (tert) gene that encodes tert. to comprehensively evaluate the association between genetic variation across this region and prca, we performed a fine-mapping analysis by genotyping 134 snps using a custom illumina iselect array or sequenom massarray iplex, followed by imputation of 1094 snps in 22 301 prca cases and 22 320 controls in the practical consortium. multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of tert that independently associated with prca risk. gene expression analysis of normal prostate tissue showed evidence that snps within one of these regions also associated with tert expression, providing a potential mechanism for predisposition to disease. © The author 2013. Published by Oxford University Press.

Published
2013

35. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Author

Michael Lush, Hans Wildiers, Christopher A. Haiman, Nils Schoof, Per Hall, Beatrice Melin, Hiltrud Brauch, Liisa M. Pelttari, Angela Brooks-Wilson, Laima Tihomirova, Ingo B. Runnebaum, Hui Cai, Kenneth Offit, Michael P. Lux, Robert Edwards, Julia A. Knight, Ignace Vergote, Arto Leminen, Alan Ashworth, Kyriaki Michailidou, Martha J. Shrubsole, Sophie Giraud, Nadeem Siddiqui, Katri Pylkäs, Sune F. Nielsen, Vernon S. Pankratz, Lenka Foretova, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Andreas du Bois, Christi J. van Asperen, Nuria Álvarez, M. Pilar Zamora, Theo A. Mvan Os, Susan J. Ramus, Olivia Fletcher, Usha Menon, Olivier Caron, Dieter Flesch-Janys, Sara H. Olson, Ellen L. Goode, Yael Laitman, Jingmei Li, Lynne R. Wilkens, Carmel Apicella, Brooke L. Fridley, Robert Luben, Mark S. Goldberg, Mary Anne Rossing, Dominique Stoppa-Lyonnet, Jonathan Beesley, Jan Lubinski, Paolo Peterlongo, Phuong L. Mai, Henrik Flyger, Thilo Dörk, Douglas A. Levine, Rob B. van der Luijt, Stig E. Bojesen, Javier Benitez, Natalia Bogdanova, Stephen J. Chanock, Andrew K. Godwin, Sharon E. Johnatty, Helga B. Salvesen, Juliet D. French, Daphne Gschwantler Kaulich, Rod Karevan, Arif B. Ekici, Marc Frenay, Taru A. Muranen, Jirong Long, Catherine S. Healey, Craig Luccarini, Chen-Yang Shen, Lorna Gibson, Pascal Guénel, Hidemi Ito, Nicholas T. Woods, Drakoulis Yannoukakos, Thomas Hansen, Francesca Damiola, Valérie Bonadona, Satoyo Hosono, Marion Piedmonte, Steve Ellis, Suleeporn Sangrajrang, Aleksandra Gentry-Maharaj, James McKay, Olga M. Sinilnikova, Jennifer A. Doherty, Xiao-Ou Shu, Curtis Olswold, Nhu D. Le, Michael J. Kerin, Malcolm C. Pike, Jenny Chang-Claude, Gianluca Severi, Michael Jones, Linda E. Kelemen, Loic Le Marchand, Maureen E. Hoatlin, Fredrick R. Schumacher, Dieter Niederacher, Michael E. Carney, Angela Cox, Attila Teoman, Hannah P. Yang, Graham G. Giles, Jianjun Liu, Xiaoqing Chen, Elisa V. Bandera, Tanja Pejovic, Galina Lurie, Karoline Kuchenbaecker, Mariusz Bidziński, Chanel E. Smart, Maartje J. Hooning, Jose Ignacio Arias Perez, Anne-Marie Gerdes, L. Rogmann, Christoph Engel, Harvey A. Risch, Ignacio Blanco, Isabel dos Santos Silva, Hoda Anton-Culver, Camilla Krakstad, Volker Arndt, Foluso O. Ademuyiwa, Frans B. L. Hogervorst, Stacey L. Edwards, Florian Heitz, Veli-Matti Kosma, Beth Y. Karlan, Robert A. Vierkant, Irene L. Andrulis, Agnieszka Dansonka-Mieszkowska, Hanne Meijers-Heijboer, Alison M. Dunning, Sabapathy P. Balasubramanian, Penny Soucy, Edwin S. Iversen, Heli Nevanlinna, Celeste Leigh Pearce, Melissa C. Southey, Howard C. Shen, Kenneth Muir, Jolanta Lissowska, Clareann H. Bunker, Judy Garber, David Van Den Berg, Yin Ling Woo, Brigitte Bressac-de Paillerets, Rebecca Hein, Norbert Arnold, Saila Kauppila, Lisa Walker, Cezary Cybulski, Estrid Høgdall, Anthony J. Swerdlow, Robert Winqvist, Susanne K. Kjaer, Christa Stegmaier, Kazuo Tajima, Caroline Baynes, Valerie Gaborieau, Keitaro Matsuo, Ed Dicks, Irene Orlow, Torben A Kruse, Rachel Palmieri Weber, David E. Goldgar, Anna Jakubowska, Honglin Song, Antonis C. Antoniou, Paul D.P. Pharoah, Katja K.H. Aben, Lambertus A. Kiemeney, Laurence Faivre, Stefan Nickels, Joellen M. Schildkraut, Yu Tang Gao, Valerie McGuire, Charles L. Shapiro, Sebastian M. Armasu, Katherine L. Nathanson, Marjanka K. Schmidt, Susan L. Neuhausen, Jolanta Kupryjanczyk, Janet E. Olson, Nicolas Wentzensen, Dong Young Noh, Maya Ghoussaini, Ian G. Campbell, Annegien Broeks, Gustavo C. Rodriguez, Rebecca L. Johnston, Shan Wang-Gohrke, Monica Barile, Vesa Kataja, Melanie Maranian, Shahana Ahmed, Christof Sohn, Julie M. Cunningham, Weiva Sieh, Shani Shimon Paluch, Riccardo Dolcetti, John W.M. Martens, Manjeet K. Bolla, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Hui Miao, Boris Winterhoff, Mari K. Halle, Arndt Hartmann, Loris Bernard, Brian E. Henderson, Els Wauters, Carl Blomqvist, Daniel O. Stram, Karen A. Pooley, Roberta B. Ness, James Paul, Hilda A. Pickett, Wei Zheng, Sandra Deming-Halverson, Soo Hwang Teo, Andrew Lee, Thomas A. Sellers, Philip Iau, D. Gareth Evans, Françis Bacot, Sunil R. Lakhani, Qin Wang, Nick Orr, Celine M. Vachon, Edith Olah, Gong Yang, Svend Aage Engelholm, Martine Dumont, Linda S. Cook, Daniel C. Tessier, Evgeny N. Imyanitov, Paolo Radice, Mikael Hartman, Annika Lindblom, John R. McLaughlin, Radka Platte, Jenny Permuth-Wey, Keun-Young Yoo, Andrew Berchuck, Roger R. Reddel, M. John Kennedy, Toru Nakanishi, Allison F. Vitonis, Melissa C. Larson, Anna H. Wu, Helmut Deissler, Giuseppe Giannini, Barbara Wappenschmidt, Tomasz Byrski, M. Kamran Ikram, Natalia Antonenkova, Banu Arun, Peter Hillemanns, William Blot, Siti Zawiah Omar, Sue Healey, Trevor Cole, Cheng Har Yip, Matthias Dürst, Mark E. Robson, Roger L. Milne, Timothy R. Rebbeck, Jaana M. Hartikainen, Mieke Kriege, C. Ellen van der Schoot, Hansjoerg Plendl, Yasushi Yatabe, Jan C. Oosterwijk, Claus Høgdall, Rob A. E. M. Tollenaar, Jacek Gronwald, Yi Lu, Kate Lawrenson, Michael D. Stutz, Chia-Ni Hsiung, Alvaro N.A. Monteiro, Maren Weischer, Philipp Harter, Nicola Miller, Lisa B. Signorello, Katarzyna Durda, Peter Lichtner, Ritu Salani, Alfons Meindl, Montserrat Garcia-Closas, George Fountzilas, Uffe Birk Jensen, Thomas Brüning, Laura Baglietto, Anne M. van Altena, Kristine M. Hillman, Bernard Peissel, Trinidad Caldés, Rosemarie Davidson, Julian Barwell, Peter Devilee, Jenny Lester, Qiuyin Cai, Heiko Müller, Jyh Cherng Yu, Kerstin Rhiem, Muy Kheng Tea, Sharon A. Savage, Åke Borg, Daniel Vincent, Antoinette Hollestelle, Katarzyna Jaworska, Mat Adenan Noor Azmi, Yon Ko, Kimberly R. Kalli, Debra Frost, Martin Gore, Chiu-Chen Tseng, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Artitaya Lophatananon, Amanda B. Spurdle, Joe Dennis, Ute Hamann, Vessela N. Kristensen, Frederik Marmé, Jonathan Tyrer, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Bruno Buecher, Kristiina Aittomäki, Kirsten B. Moysich, Lesley McGuffog, Mine S. Cicek, Guillermo Pita, Arjen R. Mensenkamp, Agnes Jager, Catherine M. Phelan, Jacques Simard, Ming-Feng Hou, Hiroji Iwata, James M. Flanagan, Elena Fineberg, Susan M. Domchek, Csilla Szabo, Diether Lambrechts, Anja Rudolph, Daehee Kang, Gottfried E. Konecny, Eitan Friedman, Argyrios Ziogas, Arto Mannermaa, Susan Peock, Matti A. Rookus, Christian F. Singer, Claire Mulot, Siranoush Manoukian, Johanna Rantala, Helen Tsimiklis, Gord Glendon, Pierre Laurent-Puig, Barbara Brouwers, Filomena Ficarazzi, Jonine D. Figueroa, Anne-Bine Skytte, Caroline Seynaeve, Christian Sutter, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Kathryn L. Terry, Børge G. Nordestgaard, Simon A. Gayther, Barbara Burwinkel, Ira Schwaab, Steven A. Narod, Elisabeth Wik, Ralf Bützow, Marco Montagna, Mark H. Greene, Linde M. Braaf, Janusz Menkiszak, Kamila Czene, Sarah Stewart-Brown, Kees E. P. van Roozendaal, Andreas Schneeweiss, Daniel Barrowdale, Elinor J. Sawyer, Alice S. Whittemore, Marc T. Goodman, Judith E. Brown, Kunle Odunsi, John L. Hopper, Nina Ditsch, Leon F.A.G. Massuger, Hermann Brenner, Joaquin J. Garcia, Xianshu Wang, Susan L. Slager, Aleksandra Tołoczko-Grabarek, Sylvie Mazoyer, Diana Eccles, Yik Ying Teo, Iwona K. Rzepecka, Bernardo Bonanni, Sara Margolin, Daniela Zaffaroni, Yew Ching Teh, Ans M Wvan Den Ouweland, Bent Ejlertsen, Maria Soller, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, J. Margriet Collée, Lorna Rodriguez-Rodriguez, Sandrina Lambrechts, Daniel W. Cramer, Douglas F. Easton, Virginie Caux-Moncoutier, Mads Thomassen, Keith Humphreys, ~, Landsteiner Laboratory, Clinical Haematology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Cardiothoracic Surgery, and Medical Oncology

Subjects
Telomerase, Messenger, Càncer d'ovari, Estrogen receptor, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, Breast cancer, Risk Factors, Alternative Splicing, Biomarkers, Tumor, Breast Neoplasms, Case-Control Studies, Chromatin, DNA Methylation, Female, Gene Expression Profiling, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Polymorphism, Single Nucleotide, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Telomere, Genetics, BUCCAL CELLS, 0303 health sciences, Tumor, Telòmer, GENETIC-VARIATION, COMMON VARIANTS, Single Nucleotide, tert-clptm1l locus, genome-wide association, genetic-variation, susceptibility loci, buccal cells, fibroblasts, common variants, carcinoma, reverse-transcriptase htert, metaanalysis, Aetiology, screening and detection Immune Regulation [ONCOL 5], 3. Good health, Tumor Markers, Biological, 030220 oncology & carcinogenesis, FIBROBLASTS, SUSCEPTIBILITY LOCI, CARCINOMA, Single-nucleotide polymorphism, Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, medicine, Polymorphism, Allele, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Breast cancer susceptibility, Hereditary cancer and cancer-related syndromes [ONCOL 1], Translational research Genomic disorders and inherited multi-system disorders [ONCOL 3], medicine.disease, Molecular biology, TERT-CLPTM1L LOCUS, Minor allele frequency, RNA, Biomarkers, REVERSE-TRANSCRIPTASE HTERT
Abstract

Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. European Commission Seventh Framework Programme (agreement 223175-HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10118 and C1287/A12014) peer-reviewed

Published
2013
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36. PPM1DMosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations

Author

Usha Menon, Jenny Lester, Alice S. Whittemore, Kunle Odunsi, Martin Widschwendter, Shashi Lele, Brooke L. Fridley, Thilo Dörk, Maria P. Intermaggio, Natalia Bogdanova, Weiva Sieh, Peter Hillemanns, David D.L. Bowtell, Ed Dicks, Caroline Baynes, Kathryn Alsop, Honglin Song, Samantha Poblete, Julie M. Cunningham, Lara E. Sucheston-Campbell, Patricia Harrington, Susan J. Ramus, Ellen L. Goode, Kirsten B. Moysich, Beth Y. Karlan, Valerie McGuire, Aleksandra Gentry-Maharaj, Mine S. Cicek, Simon A. Gayther, and Paul D.P. Pharoah

Subjects
Adult, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Brief Communication, medicine.disease_cause, Polymerase Chain Reaction, Germline, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Gene Frequency, Internal medicine, Phosphoprotein Phosphatases, medicine, Humans, Genetic Predisposition to Disease, Allele frequency, Aged, Ovarian Neoplasms, Sanger sequencing, Mutation, Massive parallel sequencing, Mosaicism, business.industry, Case-control study, High-Throughput Nucleotide Sequencing, Cancer, Middle Aged, medicine.disease, Protein Phosphatase 2C, 030104 developmental biology, Case-Control Studies, 030220 oncology & carcinogenesis, Cancer research, symbols, Female, business, Ovarian cancer
Abstract

Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC.

Published
2016
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37. Independent validation of genes and polymorphisms reported to be associated with radiation toxicity: a prospective analysis study

Author

Jonathan Tyrer, Alison M. Dunning, Vivek Misra, Jennifer S. Wilkinson, Sarah L. Gulliford, Neil G. Burnet, Caroline Baynes, Matthew R. Sydes, Paul D.P. Pharoah, Emma Hall, Don M. Conroy, David P. Dearnaley, Gillian C. Barnett, Søren M. Bentzen, Radka Platte, Craig Luccarini, Catharine M L West, Charlotte E. Coles, and Rebecca Elliott

Subjects
Oncology, Male, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Radiogenomics, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Prostate cancer, Breast cancer, Gene Frequency, Risk Factors, Internal medicine, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Prospective Studies, Prospective cohort study, Radiation Injuries, business.industry, Cancer, Prostatic Neoplasms, Dose-Response Relationship, Radiation, Odds ratio, medicine.disease, United Kingdom, Surgery, Minor allele frequency, Radiation therapy, Linear Models, Female, Radiotherapy, Adjuvant, Dose Fractionation, Radiation, Radiotherapy, Intensity-Modulated, business
Abstract

Summary Background Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset. Methods 92 (of 98 attempted) SNPs in 46 genes were successfully genotyped in 1613 patients: 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial (ISRCTN21474421, n=942) or in a prospective study of breast toxicity at the Christie Hospital, Manchester, UK (n=34). A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses. At a type I error rate adjusted for multiple testing, this study had 99% power to detect a SNP, with minor allele frequency of 0·35, associated with a per allele odds ratio of 2·2. Findings None of the previously reported associations were confirmed by this study, after adjustment for multiple comparisons. The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance. Interpretation We did not replicate previously reported late toxicity associations, suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological challenges addressed. Funding Cancer Research UK, The Royal College of Radiologists, Addenbrooke's Charitable Trust, Breast Cancer Campaign, Cambridge National Institute of Health Research (NIHR) Biomedical Research Centre, Experimental Cancer Medicine Centre, East Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer.

Published
2011

38. TGF-β signalling pathway and breast cancer susceptibility

Author

Robin Hesketh, Caroline Baynes, Douglas F. Easton, Jolanta Lissowska, Craig Luccarini, Paul D.P. Pharoah, Alison M. Dunning, Manjeet K. Humphreys, Serena Scollen, Kristy Driver, Jonine D. Figueroa, Montserrat Garcia-Closas, and James C. Metcalfe

Subjects
medicine.medical_specialty, Epidemiology, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Transforming Growth Factor beta, Internal medicine, medicine, Humans, Neoplasm Invasiveness, Prospective Studies, 030304 developmental biology, Aged, Neoplasm Staging, 0303 health sciences, Cancer, ACVRL1, Endoglin, Middle Aged, medicine.disease, Prognosis, Primary tumor, 3. Good health, Minor allele frequency, Endocrinology, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Cancer research, Female, Breast disease, Disease Susceptibility, Signal Transduction
Abstract

Background: TGF-β acts as a suppressor of primary tumor initiation but has been implicated as a promoter of the later malignant stages. Here associations with risk of invasive breast cancer are assessed for single-nucleotide polymorphisms (SNP) tagging 17 genes in the canonical TGF-β ALK5/SMADs 2&3 and ALK1/SMADs 1&5 signaling pathways: LTBP1, LTBP2, LTBP4, TGFB1, TGFB2, TGFB3, TGFBR1(ALK5), ALK1, TGFBR2, Endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, and SMAD7 [Approved Human Gene Nomenclature Committee gene names: ACVRL1 (for ALK1) and ENG (for Endoglin)]. Methods: Three-hundred-fifty-four tag SNPs (minor allele frequency > 0.05) were selected for genotyping in a staged study design using 6,703 cases and 6,840 controls from the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) study. Significant associations were meta-analyzed with data from the NCI Polish Breast Cancer Study (PBCS; 1,966 cases and 2,347 controls) and published data from the Breast Cancer Association Consortium (BCAC). Results: Associations of three SNPs, tagging TGFB1 (rs1982073), TGFBR1 (rs10512263), and TGFBR2 (rs4522809), were detected in SEARCH; however, associations became weaker in meta-analyses including data from PBCS and BCAC. Tumor subtype analyses indicated that the TGFB1 rs1982073 association may be confined to increased risk of developing progesterone receptor negative (PR−) tumors [1.18 (95% CI: 1.09–1.28), 4.1 × 10−5 (P value for heterogeneity of ORs by PR status = 2.3 × 10−4)]. There was no evidence for breast cancer risk associations with SNPs in the endothelial-specific pathway utilizing ALK1/SMADs 1&5 that promotes angiogenesis. Conclusion: Common variation in the TGF-β ALK5/SMADs 2&3 signaling pathway, which initiates signaling at the cell surface to inhibit cell proliferation, might be related to risk of specific tumor subtypes. Impact: The subtype specific associations require very large studies to be confirmed. Cancer Epidemiol Biomarkers Prev; 20(6); 1112–9. ©2011 AACR.

Published
2011

39. Functional polymorphisms in the TERT promoter are associated with risk of serous epithelial ovarian and breast cancers

Author

Angela Brooks-Wilson, Ingo B. Runnebaum, Douglas F. Easton, Tamara Marees, Evelyn Despierre, Simon A. Gayther, Aleksandra Gentry-Maharaj, Natalia Bogdanova, Kyriaki Michailidou, Roger R. Reddel, Jenny Chang-Claude, Katja K.H. Aben, Arkom Chaiwerawattana, Caroline Baynes, Usha Menon, Alina Vrieling, Ellen L. Goode, Natalia Antonenkova, Hilda A. Pickett, Lynne R. Wilkens, Nhu D. Le, Michael D. Stutz, Robert A. Vierkant, Sharon E. Johnatty, Linda S. Cook, Brooke L. Fridley, kConFab Investigators, Thilo Dörk, Abctb Investigators, Leon F.A.G. Massuger, Lorna Rodriguez-Rodriguez, Ursula Eilber, Marc T. Goodman, David N. Rider, Rachel T. Palmieri, Ignace Vergote, Sandrina Lambrechts, Sara H. Olson, Yi Lu, Surapon Wiangnon, Rayna K. Matsuno, Jun Li, Georgia Chenevix-Trench, Stuart MacGregor, Jonathan Beesley, Susan J. Ramus, Diether Lambrechts, Alison M. Dunning, Kenneth Muir, Artitaya Lophatananon, Paul D.P. Pharoah, Lambertus A. Kiemeney, Dieter Flesch-Janys, Galina Lurie, Stefan Nickels, Linda E. Kelemen, Elisa V. Bandera, Ian G. Campbell, Shan Wang-Gohrke, Shahana Ahmed, Irene Orlow, and Xiaoqing Chen

Subjects
Linkage disequilibrium, Genetics and epigenetic pathways of disease [NCMLS 6], endocrine system diseases, Genome-wide association study, 0302 clinical medicine, Neoplasms, Glandular and Epithelial, Telomerase, Ovarian Neoplasms, Genetics, 0303 health sciences, Multidisciplinary, Cancer Risk Factors, Obstetrics and Gynecology, Prognosis, Aetiology, screening and detection Immune Regulation [ONCOL 5], female genital diseases and pregnancy complications, Ovarian Cancer, Serous fluid, Oncology, 030220 oncology & carcinogenesis, Medicine, Female, Research Article, Science, Genetic Causes of Cancer, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Breast cancer, Translational research [ONCOL 3], Breast Cancer, Cancer Genetics, medicine, Humans, SNP, Allele, QH426, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Gynecologic Cancers, Cancers and Neoplasms, Human Genetics, medicine.disease, Cystadenocarcinoma, Serous, Case-Control Studies, Genetics of Disease, Genetic Polymorphism, Cancer research, Gene Function, Ovarian cancer, Gynecological Tumors, Population Genetics, RC
Abstract

Contains fulltext : 96941.pdf (Publisher’s version ) (Open Access) Genetic variation at the TERT-CLPTM1L locus at 5p15.33 is associated with susceptibility to several cancers, including epithelial ovarian cancer (EOC). We have carried out fine-mapping of this region in EOC which implicates an association with a single nucleotide polymorphism (SNP) within the TERT promoter. We demonstrate that the minor alleles at rs2736109, and at an additional TERT promoter SNP, rs2736108, are associated with decreased breast cancer risk, and that the combination of both SNPs substantially reduces TERT promoter activity.

Published
2011

40. CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen

Author

David A. Greenberg, Alison M. Dunning, Carlos Caldas, Mitul Shah, Paul D.P. Pharoah, Radka Platte, Susan Ingle, Caroline Baynes, Craig Luccarini, Kristy Driver, Bolot Kalmyrzaev, Mel Maranian, Jean Abraham, Helena M. Earl, Abraham, Jean [0000-0003-0688-4807], Earl, Helena [0000-0003-1549-8094], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Caldas, Carlos [0000-0003-3547-1489], and Apollo - University of Cambridge Repository

Subjects
Adult, Oncology, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Genotype, Breast Neoplasms, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, digestive system, Cohort Studies, Young Adult, Breast cancer, Gene Frequency, Internal medicine, medicine, Humans, skin and connective tissue diseases, Prospective cohort study, Allele frequency, Survival analysis, Aged, Proportional Hazards Models, Medicine(all), Gynecology, Proportional hazards model, business.industry, Middle Aged, medicine.disease, Survival Analysis, United Kingdom, Tamoxifen, Treatment Outcome, Cytochrome P-450 CYP2D6, Chemotherapy, Adjuvant, Female, business, Research Article, medicine.drug
Abstract

INTRODUCTION: Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen. METHODS: This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis. RESULTS: In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups. CONCLUSIONS: CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.

Published
2010
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41. Seq4SNPs: new software for retrieval of multiple, accurately annotated DNA sequences, ready formatted for SNP assay design

Author

Douglas F. Easton, Alison M. Dunning, Jonathan J. Morrison, Paul D.P. Pharoah, Craig Luccarini, Helen I. Field, Serena Scollen, Caroline Baynes, Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
dbSNP, Genotype, Sequence analysis, Computational biology, Biology, lcsh:Computer applications to medicine. Medical informatics, Biochemistry, Polymorphism, Single Nucleotide, Annotation, Software, Structural Biology, Databases, Genetic, Genotyping, Molecular Biology, lcsh:QH301-705.5, Genetics, Base Sequence, business.industry, Applied Mathematics, Computational Biology, Sequence Analysis, DNA, SNP genotyping, Computer Science Applications, ComputingMethodologies_PATTERNRECOGNITION, lcsh:Biology (General), Software design, lcsh:R858-859.7, DNA microarray, business
Abstract

Background In moderate-throughput SNP genotyping there was a gap in the workflow, between choosing a set of SNPs and submitting their sequences to proprietary assay design software, which was not met by existing software. Retrieval and formatting of sequences flanking each SNP, prior to assay design, becomes rate-limiting for more than about ten SNPs, especially if annotated for repetitive regions and adjacent variations. We routinely process up to 50 SNPs at once. Implementation We created Seq4SNPs, a web-based, walk-away software that can process one to several hundred SNPs given rs numbers as input. It outputs a file of fully annotated sequences formatted for one of three proprietary design softwares: TaqMan's Primer-By-Design FileBuilder, Sequenom's iPLEX or SNPstream's Autoprimer, as well as unannotated fasta sequences. We found genotyping assays to be inhibited by repetitive sequences or the presence of additional variations flanking the SNP under test, and in multiplexes, repetitive sequence flanking one SNP adversely affects multiple assays. Assay design software programs avoid such regions if the input sequences are appropriately annotated, so we used Seq4SNPs to provide suitably annotated input sequences, and improved our genotyping success rate. Adjacent SNPs can also be avoided, by annotating sequences used as input for primer design. Conclusion The accuracy of annotation by Seq4SNPs is significantly better than manual annotation (P < 1e-5). Using Seq4SNPs to incorporate all annotation for additional SNPs and repetitive elements into sequences, for genotyping assay designer software, minimizes assay failure at the design stage, reducing the cost of genotyping. Seq4SNPs provides a rapid route for replacement of poor test SNP sequences. We routinely use this software for assay sequence preparation. Seq4SNPs is available as a service at http://moya.srl.cam.ac.uk/oncology/bio/s4shome.html and http://moya.srl.cam.ac.uk/cgi-bin/oncology/srl/ncbi/seq4snp1.pl, currently for human SNPs, but easily extended to include any species in dbSNP.

Published
2009

42. Five polymorphisms and breast cancer risk: Results from the breast cancer association consortium

Author

Javier Benitez, José Ignacio Arias, Caroline Baynes, Keun-Young Yoo, Jyh Cherng Yu, Grethe I. Grenaker Alnæs, Alice J. Sigurdson, Irina Coinac, Don M. Conroy, Sara Margolin, Peter Devilee, Matthias W. Beckmann, Ramona Salazar, Heli Nevanlinna, Peter Schürmann, Beata Peplonska, Jolanta Lissowska, Thilo Dörk, Annika Lindblom, Peter A. Fasching, Hoda Anton-Culver, Diana Torres, Vessela N. Kristensen, Jonathan J. Morrison, Henrik Flyger, Christina Justenhoven, Sei Hyun Ahn, Manjeet K. Humphreys, Susan E. Hankinson, Argyrios Ziogoas, Ellen L. Goode, Melissa C. Southey, Fergus J. Couch, Brian E. Henderson, Doug Easton, Kati Kämpjärvi, Veli-Matti Kosma, Marjanka K. Schmidt, Ute Hamann, Amanda B. Spurdle, David G. Cox, Sandrine Tchatchou, Linda Titus-Ernstoff, Peter Kraft, Sascha Abbas, Isabel dos Santos Silva, Laura J. van't Veer, Angela Cox, Stig E. Bojesen, Tuomas Heikkinen, Kirsimari Aaltonen, Kristina Allen-Brady, Laura Baglietto, Paul D.P. Pharoah, Janet E. Olson, Daehee Kang, Christopher A. Haiman, Stephen J. Chanock, Olivia Fletcher, Laurence N. Kolonel, Maaike P.G. Vreeswijk, Jianjun Liu, Loic Le Marchand, Per Hall, Arto Mannermaa, Roger L. Milne, Saeed Rafii, Hiltrud Brauch, Gianluca Severi, Jonathan Beesley, Chen-Yang Shen, Malcolm W.R. Reed, Kamila Czene, Dieter Flesch-Janys, Rob A. E. M. Tollenaar, Claus R. Bartram, Caroline Seynaeve, Graham G. Giles, Rita K. Schmutzler, Reiner Strick, John L. Hopper, Dallas R. English, Flora E. van Leeuwen, Julian Peto, Børge G. Nordestgaard, Yuqing Li, Polly A. Newcomb, Barbara Burwinkel, Jenny Chang-Claude, Pei Ei Wu, Parveen Bhatti, Amy Trentham Dietz, Louise A. Brinton, Natalia Bogdanova, Annegien Broeks, Nicola J. Camp, Gloria Ribas, Arif B. Ekici, Nichola Johnson, Jathine Wong, Montserrat Garcia-Closas, Dong Young Noh, Vesa Kataja, Lisa A. Cannon-Albright, Karen A. Pooley, Georgia Chenevix-Trench, Hui-Chun Wang, David J. Hunter, Carmel Apicella, Alison M. Dunning, Sabapathy P. Balasubramanian, Bruce H. Alexander, Xianshu Wang, Kathleen Egan, and Mia M. Gaudet

Subjects
Oncology, Risk, medicine.medical_specialty, Genotype, Epidemiology, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Risk factor, Polymorphism, Caspase 10, Alleles, 030304 developmental biology, 0303 health sciences, Tumor Necrosis Factor-alpha, BH3 Interacting Domain Death Agonist Protein, Case-Control Studies, DNA-Binding Proteins, Europe, Female, Intracellular Signaling Peptides and Proteins, Logistic Models, Nuclear Proteins, Case-control study, Cancer, Odds ratio, Single Nucleotide, medicine.disease, 3. Good health, Minor allele frequency, Endocrinology, 030220 oncology & carcinogenesis, Breast disease
Abstract

Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610–6)

Published
2009

43. Identification of common variants in the SHBG gene affecting sex hormone binding globulin levels and breast cancer risk in postmenopausal women

Author

Dennis G. Ballinger, Robert Luben, Catherine S. Healey, Caroline Baynes, Douglas F. Easton, Shahana Ahmed, Mitch Dowsett, Paul D.P. Pharoah, Deborah J. Thompson, Alison M. Dunning, Bruce Ponder, David Cox, Elizabeth Folkerd, and Bolot Kalmyrzaev

Subjects
Risk, medicine.medical_specialty, Linkage disequilibrium, Genotype, Epidemiology, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Sex hormone-binding globulin, Breast cancer, Polymorphism (computer science), Internal medicine, Sex Hormone-Binding Globulin, polycyclic compounds, medicine, Humans, reproductive and urinary physiology, Aged, Case-control study, Cancer, Genetic Variation, Odds ratio, Middle Aged, medicine.disease, Postmenopause, Endocrinology, Oncology, Haplotypes, Case-Control Studies, biology.protein, Linear Models, Female, hormones, hormone substitutes, and hormone antagonists
Abstract

Background: Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in postmenopausal women. Three polymorphisms within the SHBG gene have been reported to affect SHBG levels, but there has been no systematic attempt to identify other such variants. Methods: We looked for associations between SHBG levels in 1,134 healthy, postmenopausal women and 11 tagging single nucleotide polymorphisms (SNP) in or around the SHBG gene. Associations between SHBG SNPs and breast cancer were tested in up to 6,622 postmenopausal breast cancer cases and 6,784 controls. Results: Ten SNPs within or close to the SHBG gene were significantly associated with SHBG levels as was the (TAAAA)n polymorphism. The best-fitting combination of rs6259, rs858521, and rs727428 and body mass index, waist, hip, age, and smoking status accounted for 24% of the variance in SHBG levels (natural logarithm transformed). Haplotype analysis suggested that rs858518, rs727428, or a variant in linkage disequilibrium with them acts to decrease SHBG levels but that this effect is neutralized by rs6259 (D356N). rs1799941 increases SHBG levels, but the previously reported association with (TAAAA)n repeat length appears to be a consequence of linkage disequilibrium with these SNPs. One further SHBG SNP was significantly associated with breast cancer (rs6257, per-allele odds ratio, 0.88; 95% confidence interval, 0.82-0.95; P = 0.002). Conclusion: At least 3 SNPs showed associations with SHBG levels that were highly significant but relatively small in magnitude. rs6257 is a potential breast cancer susceptibility variant, but relationships between the genetic determinants of SHBG levels and breast cancer are complex. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3490–8)

Published
2008

44. AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study

Author

T Wagner, Kenneth Offit, Katherine L. Nathanson, Peter Devilee, Janet E. Olson, Ilyushik E, Lenka Foretova, Jacek Gronwald, Pascaline Berthet, Muhammad Usman Rashid, Isabelle Coupier, Noralane M. Lindor, T A Sellers, Alfons Meindl, Dieter Schaefer, Shirley Hodgson, Beatrix Versmold, Olufunmilayo I. Olopade, Susan M. Domchek, Christoph Engel, Olga M. Sinilnikova, Vernon S. Pankratz, Gail E. Tomlinson, David J. Hughes, Amanda B. Spurdle, Horst J, Jakub Lubiński, Maaike P.G. Vreeswijk, Gordon Glendon, Robert A. Vierkant, Francine Durocher, Frédéric Guénard, Henry T. Lynch, Douglas F. Easton, Mary B. Daly, Susan Peock, Åke Borg, Jacques Simard, Heli Nevanlinna, Georgia Chenevix-Trench, Irene L. Andrulis, M. Cook, Caroline Baynes, Steven A. Narod, Judy Garber, Mark H. Greene, J. N. Weitzel, Patrick J. Morrison, Anna Jakubowska, Johanna Tommiska, Kristiina Aittomäki, Hans F. A. Vasen, Claudine Isaacs, Csilla Szabo, Dominique Stoppa-Lyonnet, Fergus J. Couch, Michal Zikan, Backenhorn K, Christian Sutter, Diana Torres, Antonis C. Antoniou, Ute Hamann, Andrew K. Godwin, kConFab, Rita K. Schmutzler, Tomas Kirchhoff, Susan L. Neuhausen, Zachary S. Fredericksen, Agnès Hardouin, Timothy R. Rebbeck, J. P. Struewing, and Mary Porteous

Subjects
Adult, endocrine system diseases, Tumor suppressor gene, Genotype, Epidemiology, Genes, BRCA2, Genes, BRCA1, Aneuploidy, Breast Neoplasms, Biology, Protein Serine-Threonine Kinases, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Aurora Kinases, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Allele, Age of Onset, skin and connective tissue diseases, 030304 developmental biology, Aurora Kinase A, 0303 health sciences, Oncogene, Hazard ratio, Cancer, Middle Aged, medicine.disease, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Cancer research, Female
Abstract

The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1416–21)

Published
2007

45. Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk

Author

Barbara Perkins, Robert Luben, Bob Mau, Amy Trentham-Dietz, Beth A. Aperavich, Stephanie Hesselson, Michael N. Gould, Doug Easton, Yunhong Zan, John M. Hampton, Jill D. Haag, Paul D.P. Pharoah, Caroline Baynes, Bruce A.J. Ponder, Kay-Tee Khaw, Mitul Shah, Kai-Shun Chen, David J. Samuelson, and Alison M. Dunning

Subjects
Molecular Sequence Data, Quantitative Trait Loci, Congenic, Rats, Inbred WF, Locus (genetics), Breast Neoplasms, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Rats, Inbred WKY, Breast cancer, Wisconsin, Gene Frequency, Untranslated Regions, medicine, Animals, Humans, Genetic Predisposition to Disease, Allele, Allele frequency, Crosses, Genetic, Genetics, Multidisciplinary, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Chromosome Mapping, Computational Biology, Sequence Analysis, DNA, Biological Sciences, medicine.disease, Molecular biology, Penetrance, United Kingdom, Rats, Minor allele frequency, Female, Chromosomes, Human, Pair 9
Abstract

Breast cancer risk is a polygenic trait. To identify breast cancer modifier alleles that have a high population frequency and low penetrance we used a comparative genomics approach. Quantitative trait loci (QTL) were initially identified by linkage analysis in a rat mammary carcinogenesis model followed by verification in congenic rats carrying the specific QTL allele under study. The Mcs5a locus was identified by fine-mapping Mcs5 in a congenic model. Here we characterize the Mcs5a locus, which when homozygous for the Wky allele, reduces mammary cancer risk by 50%. The Mcs5a locus is a compound QTL with at least two noncoding interacting elements: Mcs5a1 and Mcs5a2 . The resistance phenotype is only observed in rats carrying at least one copy of the Wky allele of each element on the same chromosome. Mcs5a1 is located within the ubiquitin ligase Fbxo10 , whereas Mcs5a2 includes the 5′ portion of Frmpd1 . Resistant congenic rats show a down-regulation of Fbxo10 in the thymus and an up-regulation of Frmpd1 in the spleen. The association of the Mcs5a1 and Mcs5a2 human orthologs with breast cancer was tested in two population-based breast cancer case-control studies (≈12,000 women). The minor alleles of rs6476643 ( MCS5A1 ) and rs2182317 ( MCS5A2 ) were independently associated with breast cancer risk. The minor allele of rs6476643 increases risk, whereas the rs2182317 minor allele decreases risk. Both alleles have a high population frequency and a low penetrance toward breast cancer risk.

Published
2007

46. DNA repair polymorphisms and cancer risk in non-smokers in a cohort study

Author

Elio Riboli, Ole Raaschou-Nielsen, Giuseppe Matullo, Marco Peluso, Alison M. Dunning, Aurelio Barricarte, H. B. Bueno-De-Mesquita, Gerard Hoek, Herman Autrup, J. R. Quirós, Salvatore Panico, Emmanuelle Gormally, Vittorio Krogh, Silvia Polidoro, R. Saracci, Paolo Vineis, Rudolph Kaaks, Domenico Palli, Carlos Martinez, J. Linseisen, Timothy J. Key, Luisa Airoldi, Christian Malaveille, Nicholas E. Day, P. H. M. Peeters, Fabrizio Veglia, R. Tumino, M. J. Tormo, Caroline Baynes, F. Clavel-Chapelon, Kim Overvad, Simonetta Guarrera, Eiliv Lund, Seymour Garte, H. Boeing, Miren Dorronsoro, Michal Krzyzanowski, Antonia Trichopoulou, Guillem Pera, Matullo, G, Dunning, Am, Guarrera, S, Baynes, C, Polidoro, S, Garte, S, Autrup, H, Malaveille, C, Peluso, M, Airoldi, L, Veglia, F, Gormally, E, Hoek, G, Krzyzanowski, M, Overvad, K, RAASCHOU NIELSEN, O, CLAVEL CHAPELON, F, Linseisen, J, Boeing, H, Trichopoulou, A, Palli, D, Krogh, V, Tumino, R, Panico, Salvatore, BUENO DE MESQUITA, Hb, Peeters, Ph, Lund, E, Pera, G, Martinez, C, Dorronsoro, M, Barricarte, A, Tormo, Mj, Quiros, Jr, Day, Ne, Key, Tj, Saracci, R, Kaaks, R, Riboli, E, and Vineis, P.

Subjects
Adult, Male, Risk, Oncology, Cancer Research, Pathology, medicine.medical_specialty, DNA Repair, DNA repair, Biology, non-smokers, lung, chronic obstructive pulmonary disease, Cohort Studies, Neoplasms, Internal medicine, Genotype, Odds Ratio, medicine, Humans, False Positive Reactions, Prospective Studies, ddc:610, oral-pharyngeal, Lung cancer, Prospective cohort study, Aged, Polymorphism, Genetic, Bladder cancer, Smoking, Haplotype, Case-control study, Cancer, General Medicine, Middle Aged, medicine.disease, DNA repair polymorphisms, laryngeal cancer, leukaemia, Case-Control Studies, Multivariate Analysis, Female
Abstract

Environmental carcinogens contained in air pollution, such as polycyclic aromatic hydrocarbons, aromatic amines or N-nitroso compounds, predominantly form DNA adducts but can also generate interstrand cross-links and reactive oxygen species. If unrepaired, such lesions increase the risk of somatic mutations and cancer. Our study investigated the relationships between 22 polymorphisms (and their haplotypes) in 16 DNA repair genes belonging to different repair pathways in 1094 controls and 567 cancer cases (bladder cancer, 131; lung cancer, 134; oral-pharyngeal cancer, 41; laryngeal cancer, 47; leukaemia, 179; death from emphysema and chronic obstructive pulmonary disease, 84). The design was a case-control study nested within a prospective investigation. Among the many comparisons, few polymorphisms were associated with the diseases at the univariate analysis: XRCC1-399 Gln/Gln variant homozygotes [odds ratios (OR) = 2.20, 95% confidence intervals (CI) = 1.16-4.17] and XRCC3-241 Met/Met homozygotes (OR = 0.51, 95% CI = 0.27-0.96) and leukaemia. The recessive model in the stepwise multivariate analysis revealed a possible protective effect of XRCC1-399Gln/Gln in lung cancer (OR = 0.22, 95% CI = 0.05-0.98), and confirmed an opposite effect (OR = 2.47, 95% CI = 1.02-6.02) in the leukaemia group. Our results also suggest that the XPD/ERCC1-GAT haplotype may modulate leukaemia (OR = 1.28, 95% CI = 1.02-1.61), bladder cancer (OR = 1.38, 95% CI = 1.06-1.79) and possibly other cancer risks. Further investigations of the combined effects of polymorphisms within these DNA repair genes, smoking and other risk factors may help to clarify the influence of genetic variation in the carcinogenic process. © 2006 Oxford University Press.

Published
2006

47. IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer

Author

Paula Smith, Barbara Perkins, Paul D.P. Pharoah, Nicholas J. Wareham, Karen A. Pooley, Douglas F. Easton, Caroline Baynes, Bruce A.J. Ponder, Manjinder S. Sandhu, Ali Al-Zahrani, Craig Luccarini, Deborah J. Thompson, Alison M. Dunning, Hannah Munday, and Robert Luben

Subjects
Oncology, Male, medicine.medical_specialty, Population, IGFBP3, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Breast cancer, Internal medicine, Genetics, medicine, SNP, Humans, Genetic Predisposition to Disease, Allele, Insulin-Like Growth Factor I, education, Molecular Biology, Genetics (clinical), education.field_of_study, General Medicine, Odds ratio, medicine.disease, Confidence interval, Endocrinology, Insulin-Like Growth Factor Binding Protein 3, England, Female
Abstract

Experimental and observational studies in humans and animals suggest that insulin-like growth factor 1 (IGF1) and its principal binding protein, IGFBP3, may influence breast cancer susceptibility. We have exam- ined the association of nine and four single nucleotide polymorphisms (SNPs) in the IGF1 gene and in the IGFBP3 genes, respectively, with circulating levels of their gene products in a population-based study of 600 middle-aged men and women, and in a breast cancer case-control study, comprised 4647 cases and 4564 controls. All study participants are from the East Anglian region of UK. SNPs were specifically chosen to tag all other known SNPs in each gene. Several SNPs in each gene are associated both with cir- culating levels of their respective proteins and with risk of breast cancer. In particular, the c allele of IGF1 SNPrs1520220 is associated with increased circulating IGF1 (r 2 5 2.1%, P-trend 5 0.003) in females and an increased risk of breast cancer: odds ratio (OR) (cc/gg) 5 1.41; 95% confidence intervals (95% CI) 1.11-1.79, P-trend 5 0.03. The a allele of IGFBP3 SNP rs2854744 is associated with increased circulating IGFBP3 (r 2 5 9.7%, P < 10 29 ) and a decreased risk of breast cancer: OR (aa/cc) 5 0.87; 95% CI 0.77-0.99, P 5 0.03. Our data indicate that common variants in the IGF1 and IGFBP3 genes are associated with differ- ences in circulating levels of IGF1 and IGFBP3 and with breast cancer risk. More specifically and consistent with experimental models, our data suggest that higher IGF1 levels may increase the risk of breast cancer but higher IGFBP3 levels may be protective.

Published
2005

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

Author

William J. Tapper, Frederik Marmé, Natalia Bogdanova, Joe Dennis, Pei-Ei Wu, Vesa Kataja, Michael Jones, Dong-Young Noh, Xiaoqing Chen, Thilo Dörk, Javier Benitez, Arif B. Ekici, André G. Uitterlinden, Karin Leunen, Chen-Yang Shen, Esther M. John, Sune F. Nielsen, Adam M. Lee, Arto Mannermaa, Dieter Flesch-Janys, Diana Eccles, Don M. Conroy, Quinten Waisfisz, Sara Margolin, Hoda Anton-Culver, Peter Devilee, Ans M.W. van den Ouweland, Ruth Swann, Chia-Ni Hsiung, Peter Schürmann, Per Hall, Bertram Müller-Myhsok, Jonathan Beesley, Graham G. Giles, Qin Wang, Mitul Shah, Matthias W. Beckmann, Veli-Matti Kosma, Carmel Apicella, Henrik Flyger, Daniel F. Schmidt, Gianluca Severi, Kristen N. Stevens, Paolo Peterlongo, Helen Tsimiklis, Betül T. Yesilyurt, Irene L. Andrulis, Louiza S. Velentzis, Peter A. Fasching, Jyh-Cherng Yu, Caroline Baynes, Jenny Chang-Claude, Craig Luccarini, Leslie Bernstein, Katarzyna Durda, Antoinette Hollestelle, Catriona McLean, Georgia Chenevix-Trench, Rebecca Hein, Heli Nevanlinna, Arja Jukkola-Vuorinen, Jolanta Lissowska, Rita K. Schmutzler, Giuseppe Floris, Christa Stegmaier, David J. Hunter, Kristiina Aittomäki, Johann H. Karstens, Alan Ashworth, Alfons Meindl, Emilie Cordina-Duverger, Stefan Nickels, Julian Peto, Jan Lubinski, Børge G. Nordestgaard, Ed Dicks, Stig E. Bojesen, Christie J. van Asperen, Malcolm W.R. Reed, Michael J. Kerin, Annika Lindblom, Barbara Burwinkel, Kristy Driver, Darya Prokofieva, Montserrat Garcia-Closas, Thomas Brüning, Christina Justenhoven, Nazneen Rahman, Annegien Broeks, Hermann Brenner, Hiltrud Brauch, Laura Baglietto, Yuri I. Rogov, Clare Turnbull, A Jakubowska, Marina Bermisheva, Heiko Müller, Hanne Meijers-Heijboer, Anne-Lise Børrensen-Dale, Pascal Guénel, Stephen J. Chanock, Siranoush Manoukian, Melissa C. Southey, Daniel J. Park, M. Rosario Alonso, Christof Sohn, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Jonine D. Figueroa, Robert Winqvist, Jianjun Liu, Suthee Rattanamongkongul, Diether Lambrechts, Andreas Schneeweiss, Paul D.P. Pharoah, Alexander Miron, Ursula Eilber, Angela Cox, Anna González-Neira, Minh Bui, Frans B. L. Hogervorst, Peter Hillemanns, Peter Lichtner, Maartje J. Hooning, Roger L. Milne, Alison M. Dunning, Fernando Rivadeneira, Ian Tomlinson, Thérèse Truong, Volker Arndt, Rogier A. Oldenburg, Grethe I. Grenaker Alnæs, Senno Verhoef, Rob A. E. M. Tollenaar, Anna Marie Mulligan, Kenneth Muir, Christina Clarke Dur, Katarzyna Jaworska, Saila Kauppila, Olivia Fletcher, Jaana M. Hartikainen, Michael P. Lux, Kyriaki Michailidou, Stefano Fortuzzi, Douglas F. Easton, Anthony J. Swerdlow, Elza Khusnutdinova, Annie Perkins, Carl Blomqvist, Argyrios Ziogas, Keun-Young Yoo, Caroline Seynaeve, Natalia Antonenkova, Bruce A.J. Ponder, Vessela N. Kristensen, Gord Glendon, Daehee Kang, Elinor J. Sawyer, Michael Bremer, Louise A. Brinton, Minouk J. Schoemaker, Kamila Czene, Isabel dos Santos Silva, John L. Hopper, Astrid K. Irwanto, Nick Orr, S Gerty, Fergus J. Couch, Arkom Chaiwerawattana, Manjeet K. Humphreys, Marjanka K. Schmidt, Maya Ghoussaini, Nikki Graham, Artitaya Lophatananon, Florence Menegaux, Enes Makalic, Katri Pylkäs, Nichola Johnson, Xianshu Wang, Bernardo Bonanni, Mark Lathrop, Human genetics, CCA - Oncogenesis, Clinical Genetics, Internal Medicine, Medical Oncology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, and Human Genetics

Subjects
Candidate gene, Chromosomes,Human,Pair 21, analysis, cell carcinoma, Mammary gland, Estrogen receptor, Genome-wide association study, developmental regulatory molecule, 0302 clinical medicine, common variants, retinoic acid, Pair 12, genetics, hormone-related protein, Genetics, Chromosomes,Human,Pair 12, Treatment - Localised Therapies – Discovery and Development, Principal Component Analysis, 0303 health sciences, Bone metastasis, Single Nucleotide, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, epidemiology, Cancer Type - Breast Cancer, Female, Human, Risk, ulnar-mammary syndrome, parathyroid-hormone, European Continental Ancestry Group, Breast Neoplasms, Biology, Chromosomes, Polymorphism,Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Genetic predisposition, medicine, cancer, Humans, Women, Genetic Predisposition to Disease, Polymorphism, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], breast, 030304 developmental biology, Hereditary cancer and cancer-related syndromes [ONCOL 1], Cancer, confer susceptibility, medicine.disease, gene-expression, Logistic Models, negative-feedback, Genetic Loci, Cancer research, Other, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Pair 21, Meta-Analysis
Abstract

Item does not contain fulltext Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for approximately 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in approximately 70,000 cases and approximately 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 x 10(-35)), 12q24 (rs1292011; P = 4.3 x 10(-19)) and 21q21 (rs2823093; P = 1.1 x 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
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49. 116 A validation study of 68 single nucleotide polymorphisms which have been associated with radiation toxicity: preliminary results of the RAPPER study

Author

Gillian C. Barnett, Rebecca Elliott, Caroline Baynes, Alison M. Dunning, Craig Luccarini, Don M. Conroy, J.S. Wilkinson, Neil G. Burnet, Catharine M L West, and Charlotte E. Coles

Subjects
Genetics, Cancer Research, Validation study, Oncology, Toxicity, Single-nucleotide polymorphism, Biology
Published
2010
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50. Erratum: Corrigendum: A common coding variant in CASP8 is associated with breast cancer risk

Author

Frans B. L. Hogervorst, Suleeporn Sangrajrang, Alison M. Dunning, Sabapathy P. Balasubramanian, Per Hall, Malcolm W.R. Reed, Graham G. Giles, Louise A. Brinton, David J. Hughes, Fabrice Odefrey, Heli Nevanlinna, Laura J. van't Veer, Sara Wedrén, Angela Risch, Caroline Baynes, Jolanta Lissowska, John L. Hopper, Douglas F. Easton, Lorna Gibson, Diana Torres, Alice J. Sigurdson, Christina Justenhoven, Melissa C. Southey, Dong Young Noh, Silke Kropp, Vesa Kataja, Javier Benitez, Daehee Kang, Angela Cox, Paul D.P. Pharoah, Isabel dos Santos Silva, Karen A. Pooley, Bruce H. Alexander, Janet E. Olson, Roger L. Milne, Fergus J. Couch, Rainer Fagerholm, Carl Blomqvist, Keun-Young Yoo, Jaana M. Hartikainen, Georgia Chenevix-Trench, Montserrat Garcia-Closas, Serena Scollen, Gloria Ribas, Ute Hamann, Jenny Chang-Claude, Anna González-Neira, Shan Wang-Gohrke, Kirsimari Aaltonen, Jeffery P. Struewing, Hiltrud Brauch, Jianjun Liu, Ellen L. Goode, Bruce A.J. Ponder, Olivia Fletcher, Stephen J. Chanock, Natalia Bogdanova, Stig E. Bojesen, Paul Brennan, Nazneen Rahman, Anthony Renwick, Sheila Seal, C K Axelsson, Peter Schürmann, Annegien Broeks, Michael R. Stratton, Margaret R. E. McCredie, Jonathan Beesley, Yen-Ling Low, Thilo Dörk, Marjanka K. Schmidt, Veli Matti Kosma, Amanda B. Spurdle, Arto Mannermaa, Sei Hyun Ahn, Nichola Johnson, Denise L. Stredrick, Børge G. Nordestgaard, and Beata Peplonska

Subjects
Minor allele frequency, Oncology, medicine.medical_specialty, Breast cancer, Internal medicine, Genotype, Genetics, medicine, SNP, Odds ratio, Biology, medicine.disease, Confidence interval
Abstract

Nat. Genet. 39, 352–358 (2007); published online 11 February 2007; corrected 10 April 2007 In the version of this article initially published, there was an error that affected the calculations of the odds ratios, confidence intervals, between-study heterogeneity, trend test and test for association for SNP ICAM5 V301I in Table 1 (ICAM5 V301I); genotype counts in Supplementary Table 2 (ICAM5; ICR_FBCS and Kuopio studies) and minor allele frequencies, trend test and odds ratios for heterozygotes and rare homozygotes in Supplementary Table 3 (ICAM5; ICR_FBCS and Kuopio studies).

Published
2007
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