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1. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

Author: Madalene Earp, Jonathan P Tyrer, Stacey J Winham, Hui-Yi Lin, Ganna Chornokur, Joe Dennis, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Høgdall, Satoyo Hosono, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Audrey Y Jung, Beth Y Karlan, Melissa Kellar, Lambertus A Kiemeney, Boon Kiong Lim, Susanne K Kjaer, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Shashi Lele, Jenny Lester, Douglas A Levine, Zheng Li, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, James Paul, Tanja Pejovic, Liisa M Pelttari, Jenny B Permuth, Malcolm C Pike, Elizabeth M Poole, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Ingo B Runnebaum, Iwona K Rzepecka, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston-Campbell, Ingvild L Tangen, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Shelley S Tworoger, Anne M van Altena, Ignace Vergote, Liv Cecilie Vestrheim Thomsen, Robert A Vierkant, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Yin-Ling Woo, Anna H Wu, Xifeng Wu, Yong-Bing Xiang, Hannah Yang, Wei Zheng, Argyrios Ziogas, Alice W Lee, Celeste L Pearce, Andrew Berchuck, Joellen M Schildkraut, Susan J Ramus, Alvaro N A Monteiro, Steven A Narod, Thomas A Sellers, Simon A Gayther, Linda E Kelemen, Georgia Chenevix-Trench, Harvey A Risch, Paul D P Pharoah, Ellen L Goode, and Catherine M Phelan
Subjects: Medicine, Science
Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
Published: 2018
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2. Dietary Supplement Use and Colorectal Adenoma Risk in Individuals with Lynch Syndrome: The GEOLynch Cohort Study.

Author: Renate C Heine-Bröring, Renate M Winkels, Akke Botma, Fränzel J B van Duijnhoven, Audrey Y Jung, Jan H Kleibeuker, Fokko M Nagengast, Hans F A Vasen, and Ellen Kampman
Subjects: Medicine, Science
Abstract: Individuals with Lynch syndrome have a high lifetime risk of developing colorectal tumors. In this prospective cohort study of individuals with Lynch syndrome, we examined associations between use of dietary supplements and occurrence of colorectal adenomas.Using data of 470 individuals with Lynch syndrome in a prospective cohort study, associations between dietary supplement use and colorectal adenoma risk were evaluated by calculating hazard ratios (HR) and 95% confidence intervals (CI) using cox regression models adjusted for age, sex, and number of colonoscopies during person time. Robust sandwich covariance estimation was used to account for dependency within families.Of the 470 mismatch repair gene mutation carriers, 122 (26.0%) developed a colorectal adenoma during an overall median person time of 39.1 months. 40% of the study population used a dietary supplement. Use of any dietary supplement was not statistically significantly associated with colorectal adenoma risk (HR = 1.18; 95%CI 0.80-1.73). Multivitamin supplement use (HR = 1.15; 95%CI 0.72-1.84), vitamin C supplement use (HR = 1.57; 95%CI 0.93-2.63), calcium supplement use (HR = 0.69; 95%CI 0.25-1.92), and supplements containing fish oil (HR = 1.60; 95%CI 0.79-3.23) were also not associated with occurrence of colorectal adenomas.This prospective cohort study does not show inverse associations between dietary supplement use and occurrence of colorectal adenomas among individuals with Lynch syndrome. Further research is warranted to determine whether or not dietary supplement use is associated to colorectal adenoma and colorectal cancer risk in MMR gene mutation carriers.
Published: 2013
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3. No effect of folic acid supplementation on global DNA methylation in men and women with moderately elevated homocysteine.

Author: Audrey Y Jung, Yvo Smulders, Petra Verhoef, Frans J Kok, Henk Blom, Robert M Kok, Ellen Kampman, and Jane Durga
Subjects: Medicine, Science
Abstract: A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; n = 105) or placebo treatment (n = 111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (difference = 0.008, 95%CI = -0.05,0.07, P = 0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, n = 76; CT, n = 70; TT, n = 70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes.ClinicalTrials.gov NCT00110604.
Published: 2011
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4. Postdiagnosis circulating osteoprotegerin and TRAIL concentrations and survival and recurrence after a breast cancer diagnosis: results from the MARIE patient cohort

Author: Charlotte Le Cornet, Audrey Y. Jung, Theron S. Johnson, Sabine Behrens, Nadia Obi, Heiko Becher, Jenny Chang-Claude, and Renée T. Fortner
Subjects: OPG, TRAIL, Breast cancer survival, Estrogen receptor status, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Experimental studies suggest a role for osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in mammary tumor development and progression. These biomarkers have been minimally investigated with respect to outcomes in breast cancer patients. Methods OPG and TRAIL were evaluated in blood samples collected from 2459 breast cancer patients enrolled in the MARIE study, a prospective population-based patient cohort, at median of 129 days after diagnosis. Participants were between ages 50 and 74 at diagnosis and recruited from 2002 to 2005 in two regions of Germany. Follow-up for recurrence and mortality was conducted through June 2015. Delayed-entry Cox proportional hazards regression was used to assess associations between OPG and TRAIL with all-cause and breast cancer-specific mortality, and recurrence, both overall and by tumor hormone receptor status. Results Median follow-up time was 11.7 years, with 485 deaths reported (277 breast cancer-specific). Higher OPG concentrations were associated with a higher risk of all-cause mortality (hazard ratio for 1-unit log2-transformed concentration (HRlog2) = 1.24 (95% confidence interval 1.03–1.49). Associations were observed in women diagnosed with ER-PR- tumors or discordant hormone receptor status (ER-PR-, HRlog2 = 1.93 (1.20–3.10); discordant ERPR, 1.70 (1.03–2.81)), but not for women with ER + PR + tumors (HRlog2 = 1.06 (0.83–1.35)). OPG was associated with a higher risk of recurrence among women with ER-PR- disease (HRlog2 = 2.18 (1.39–3.40)). We observed no associations between OPG and breast cancer-specific survival, or for TRAIL and any outcome. Conclusions Higher circulating OPG may be a biomarker of a higher risk of poor outcome among women diagnosed with ER- breast cancer. Further mechanistic studies are warranted.
Published: 2023
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5. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Anna Morra, Maria Escala-Garcia, Jonathan Beesley, Renske Keeman, Sander Canisius, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Annelie Augustinsson, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Thomas Brüning, Saundra S. Buys, Bette Caan, Daniele Campa, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Ting-Yuan David Cheng, Christine L. Clarke, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Thilo Dörk, Laure Dossus, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Lin Fritschi, Manuela Gago-Dominguez, José A. García-Sáenz, Graham G. Giles, Mervi Grip, Pascal Guénel, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Steven N. Hart, Jaana M. Hartikainen, Arndt Hartmann, Wei He, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Anthony Howell, David J. Hunter, ABCTB Investigators, kConFab Investigators, Agnes Jager, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Machteld Keupers, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Martha Linet, Robert N. Luben, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Kyriaki Michailidou, Roger L. Milne, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Andrew F. Olshan, Håkan Olsson, Nick Orr, Tjoung-Won Park-Simon, Alpa V. Patel, Bernard Peissel, Paolo Peterlongo, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Brigitte Rack, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Matthias Ruebner, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Andreas Schneeweiss, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Lauren R. Teras, Mary Beth Terry, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Qin Wang, Amber N. Hurson, Robert Winqvist, Alicja Wolk, Argyrios Ziogas, Hiltrud Brauch, Montserrat García-Closas, Paul D. P. Pharoah, Douglas F. Easton, Georgia Chenevix-Trench, and Marjanka K. Schmidt
Subjects: Common germline genetic variants, Breast cancer-specific survival, Patient subgroups, Tumor biology, Systemic treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP
Published: 2021
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6. Pre- to postdiagnosis leisure-time physical activity and prognosis in postmenopausal breast cancer survivors

Author: Audrey Y. Jung, Sabine Behrens, Martina Schmidt, Kathrin Thoene, Nadia Obi, Anika Hüsing, Axel Benner, Karen Steindorf, and Jenny Chang-Claude
Subjects: Breast cancer, Prognosis, Survival, Physical activity, Postmenopausal, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Physical activity (PA) before and after breast cancer diagnosis has been reported to be associated with lower mortality. However, whether changes in the activity after diagnosis impact prognosis is unclear and has not received much attention. This study aimed to examine pre- to postdiagnosis leisure-time PA and breast cancer prognosis. Methods We used data from the MARIE study, a prospective population-based patient cohort study of 3813 postmenopausal breast cancer patients, aged 50–74 at diagnosis, recruited from 2002 to 2005, re-interviewed in 2009, and followed up until June 2015. Prediagnosis PA was assessed at recruitment; postdiagnosis PA was assessed at re-interview in 2009. To examine pre- to postdiagnosis change in PA, women were categorized by pre- and postdiagnosis PA using a cut-off of 7.5 MET-h/week for meeting PA recommendations and combined into four groups: insufficiently active, increasingly active, decreasingly active, and sufficiently active. Cox regression models with delayed entry were used to assess associations between pre- to postdiagnosis patterns of PA and overall mortality (OM), breast cancer mortality (BCM), and recurrence-free survival (RFS). Additional analyses of pre- and postdiagnosis PA (no activity (reference), low activity, sufficient activity) with cancer outcomes, such as using a time-dependent model, were performed. In total, 2042 patients were included in the analyses. Results There were 206 deaths (114 from breast cancer) after a median follow-up time of 6.0 years after the 2009 interview. Compared to insufficiently active women, increasingly active women were at lower risk of OM, BCM, and RFS (HR (95%CI) of 0.50 (0.31–0.82), 0.54 (0.30–1.00), 0.58 (0.40–0.84), respectively). In sufficiently active women, associations for OM (0.75 (0.48–1.15)), BCM (0.61 (0.33–1.13)), and RFS 0.80 (0.57–1.14)) were similar to increasingly active women but attenuated, and decreasingly active women were not at lower risk for OM (0.91 (0.61–1.36)), BCM (0.80 (0.45–1.42)), and RFS (1.04 (0.76–1.43)). In time-dependent analyses, sufficient activity vs. no activity was associated with better OM (0.73 (0.57–0.93)), BCM (0.64 (0.46–0.89)), and RFS (0.82 (0.68–0.99)). Low activity was not significantly associated with prognosis. Conclusion Our data support benefits for breast cancer prognosis in being physically active pre- and postdiagnosis particularly for women who were insufficiently active prediagnosis.
Published: 2019
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7. The impact of coding germline variants on contralateral breast cancer risk and survival

Author: Anna Morra, Nasim Mavaddat, Taru A. Muranen, Thomas U. Ahearn, Jamie Allen, Irene L. Andrulis, Päivi Auvinen, Heiko Becher, Sabine Behrens, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Nicola J. Camp, Sara Carvalho, Jose E. Castelao, Melissa H. Cessna, Jenny Chang-Claude, Georgia Chenevix-Trench, Kamila Czene, Brennan Decker, Joe Dennis, Thilo Dörk, Leila Dorling, Alison M. Dunning, Arif B. Ekici, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Willemina R.R. Geurts-Giele, Graham G. Giles, Pascal Guénel, Melanie Gündert, Eric Hahnen, Per Hall, Ute Hamann, Patricia A. Harrington, Wei He, Päivi Heikkilä, Maartje J. Hooning, Reiner Hoppe, Anthony Howell, Keith Humphreys, Anna Jakubowska, Audrey Y. Jung, Renske Keeman, Vessela N. Kristensen, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger L. Milne, Anna Marie Mulligan, William G. Newman, Tjoung-Won Park-Simon, Paolo Peterlongo, Paul D.P. Pharoah, Valerie Rhenius, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Amanda B. Spurdle, Ian Tomlinson, Thérèse Truong, Elke M. van Veen, Maaike P.G. Vreeswijk, Qin Wang, Camilla Wendt, Xiaohong R. Yang, Heli Nevanlinna, Peter Devilee, Douglas F. Easton, Marjanka K. Schmidt, Kristine K. Sahlberg, Anne-Lise Børresen-Dale, Inger Torhild Gram, Karina Standahl Olsen, Olav Engebråten, Bjørn Naume, Jürgen Geisler, null OSBREAC, Grethe I. Grenaker Alnæs, David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret Cummings, Sarah-Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Jason Lee, Shuai Li, Geoff Lindeman, Lara Lipton, Liz Lobb, Sherene Loi, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Jia-Min Pang, Gargi Pathak, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Susan Ramus, Edwina Rickard, Bridget Robinson, Mona Saleh, Anita Skandarajah, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Rodney Scott, Clare Scott, Adrienne Sexton, Andrew Shelling, Peter Simpson, Melissa Southey, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young, and Milita Zaheed
Subjects: Genetics, Genetics (clinical)
Abstract: Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.
Published: 2023

8. Breast cancer risk factors and survival by tumor subtype

Author: Päivi Auvinen, Hoda Anton-Culver, Stig E. Bojesen, Gad Rennert, Christos Petridis, Taru A. Muranen, Lukas Schwentner, Jenny Chang-Claude, Chen-Yang Shen, Melissa A. Troester, Sara Y. Brucker, Miriam Dwek, Jingmei Li, Nadia Obi, Montserrat Garcia-Closas, Soo Hwang Teo, Pascal Guénel, Hidemi Ito, Sabine Behrens, Rulla M. Tamimi, Melissa C. Southey, Michelle D. Holmes, Christopher A. Haiman, Henrik Flyger, Roger L. Milne, Per Hall, Jyh-Cherng Yu, Thomas U. Ahearn, William G. Newman, D. Gareth Evans, Dong-Young Noh, Qin Wang, Robert Winqvist, Tjoung-Won Park-Simon, Angela Cox, Dimitrios Mavroudis, Federico Canzian, Celine M. Vachon, Annelie Augustinsson, Shivaani Mariapun, Keitaro Matsuo, Mia M. Gaudet, Anna Jakubowska, Loic Le Marchand, Rob A. E. M. Tollenaar, Paul D.P. Pharoah, Mikael Hartman, Jane Heyworth, Alison M. Dunning, Daniele Campa, Keun-Young Yoo, Anna Morra, Sileny Han, Anna H. Wu, David J. Hunter, Laura E. Beane Freeman, Mehdi Manoochehri, Volker Arndt, Elinor J. Sawyer, Peter A. Fasching, Alicja Wolk, Xiao-Ou Shu, José A. García-Sáenz, Hermann Brenner, Børge G. Nordestgaard, Pooja Middha Kapoor, Diether Lambrechts, Kamila Czene, Marjanka K. Schmidt, Nadege Presneau, Stephen J. Chanock, Mervi Grip, Ignacio Briceño, Stella Koutros, Nicola J. Camp, Kathleen M. Egan, Wei Zheng, Reiner Hoppe, Simon S. Cross, James V. Lacey, Manjeet K. Bolla, Cari M. Kitahara, Annika Lindblom, Carl Blomqvist, William J. Tapper, Diana Torres, Jan Lubinski, Milena Jakimovska, Vessela N. Kristensen, Jose E. Castelao, Graham G. Giles, Andrew F. Olshan, John L. Hopper, A. Heather Eliassen, Valerie Rhenius, Christopher G. Scott, Agnes Jager, Thilo Dörk, Justin A. Williams, Ian Tomlinson, Emmanouil Saloustros, Ji Yeob Choi, Dijana Plaseska-Karanfilska, Thérèse Truong, Audrey Y. Jung, Daehee Kang, Argyrios Ziogas, Peter Kraft, Arto Mannermaa, Rudolf Kaaks, Heiko Becher, Wolfgang Janni, Niclas Håkansson, Steven N. Hart, Xiaohong R. Yang, Håkan Olsson, Fergus J. Couch, Renske Keeman, Ute Hamann, Atocha Romero, Daniel O. Stram, Andreas Schneeweiss, Susan M. Gapstur, Michael Lush, Diana Eccles, Sara Margolin, Hedy S. Rennert, Muhammad Usman Rashid, Mitul Shah, Matthias W. Beckmann, Sophia S. Wang, Douglas F. Easton, Manuela Gago-Dominguez, Christine L. Clarke, and Medical Oncology
Subjects: 0301 basic medicine, Oncology, Adult, medicine.medical_specialty, Epidemiology, Estrogen receptor, Breast Neoplasms, Article, 03 medical and health sciences, Aged, Cause of Death, Female, Humans, Middle Aged, Neoplasm Invasiveness, Neoplasm Staging, Prospective Studies, Risk Factors, Survival Analysis, Life Style, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, business.industry, Proportional hazards model, Cancer, medicine.disease, Confidence interval, 3. Good health, Tumor Subtype, 030104 developmental biology, Clinical research, 030220 oncology & carcinogenesis, business, Body mass index
Abstract: Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
Published: 2021

9. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Ana Peixoto, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Michael Untch, Susan J. Ramus, Kenneth Offit, John J. Spinelli, Clarice R. Weinberg, Kyriaki Michailidou, Javier Benitez, Rita K. Schmutzler, Lizet E. van der Kolk, Heli Nevanlinna, Annika Lindblom, Sara Margolin, Stella Koutros, Elza Khusnutdinova, Diana Eccles, Lenka Foretova, Wolfgang Janni, Jennifer T. Loud, Roger L. Milne, Patrick Neven, Thomas U. Ahearn, Hedy S. Rennert, Karolina Prajzendanc, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Pascal Guénel, Antoinette Hollestelle, Jolanta Lissowska, Ni Zhao, Melissa Christiaens, Hoda Anton-Culver, Ans M.W. van den Ouweland, Christopher A. Haiman, Debra Frost, Vessela N. Kristensen, Bernard Peissel, Muhammad Usman Rashid, Noura Mebirouk, Claudine Isaacs, Matthias W. Beckmann, Sofia Khan, Xia Jiang, Jack A. Taylor, Peter Hillemanns, Robert Winqvist, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Katherine L. Nathanson, Judy Garber, Siranoush Manoukian, Simon S. Cross, Flavio Lejbkowicz, Manjeet K. Bolla, Goska Leslie, Saundra S. Buys, Banu Arun, Xiaohong R. Yang, Peter Schürmann, Irene Konstantopoulou, Mia M. Gaudet, Rob A. E. M. Tollenaar, Joe Dennis, Louise Izatt, David E. Goldgar, Anna Jakubowska, Alicja Lukomska, Fabienne Lesueur, Susanna C. Larsson, Peter Devilee, Helen Byers, Bernd Holleczek, Marc Tischkowitz, Arif B. Ekici, Austin Miller, Carl Blomqvist, Christopher R. Hake, Paul D.P. Pharoah, Harvey A. Risch, Kristin K. Zorn, Mehdi Manoochehri, Kamila Czene, Peter A. Fasching, Trinidad Caldés, Hanna Huebner, Agnes Jager, William G. Newman, Lesley McGuffog, Maren T. Scheuner, Nick Orr, Susan M. Domchek, Antonis C. Antoniou, Peter Kraft, Pooja Middha Kapoor, Daniel R. Barnes, Christine L. Clarke, Douglas F. Easton, Bernadette A M Heemskerk-Gerritsen, Ross L. Prentice, Mark E. Sherman, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Diether Lambrechts, Mark H. Greene, Mark S. Goldberg, Peter J. Hulick, Maria Elena Martinez, Arto Mannermaa, Frans B. L. Hogervorst, Christian F. Singer, Johanna Rantala, Esther M. John, Jesse Nodora, Wendy K. Chung, Csilla Szabo, Mads Thomassen, Tracy A. O'Mara, Kelly-Anne Phillips, Manuela Gago-Dominguez, Jacques Simard, John L. Hopper, Jacopo Azzollini, Rudolf Kaaks, Haoyu Zhang, Eitan Friedman, Heiko Becher, János Papp, Thomas Rüdiger, Alison M. Dunning, Daniele Campa, Alfons Meindl, Lothar Häberle, Ana Blanco, Eric Hahnen, Barbara Wappenschmidt, Elaine F. Harkness, Audrey Y. Jung, Guanghao Qi, Zumuruda Abu Ful, Maria A. Caligo, Priyanka Sharma, Håkan Olsson, Elke M van Veen, Marion Piedmonte, Linetta B. Koppert, Usha Menon, Laura Matricardi, Jonine D. Figueroa, Wei Zheng, Milena Jakimovska, Katarzyna Białkowska, Renske Keeman, Matti A. Rookus, William J. Tapper, J. Peto, Paul L. Auer, Andreas Schneeweiss, Xiao-Ou Shu, Miriam Dwek, Elvira Mingazheva, Hermann Brenner, Emilija Lazarova, Atocha Romero, Rulla M. Tamimi, Laura Papi, Hans Wildiers, Catriona McLean, Montserrat Garcia-Closas, Matthias Rübner, Thomas Brüning, Graham G. Giles, Robert J. MacInnis, Hans Christiansen, Sten Cornelissen, Paul A. James, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Nilanjan Chatterjee, D. Gareth Evans, Ignacio Briceño, Mary B. Daly, Annegien Broeks, Evgeny N. Imyanitov, Jonathan Beesley, Snezhana Smichkoska, Thilo Dörk, Yon-Dschun Ko, Paolo Peterlongo, Celine M. Vachon, Claire Mulot, Kristiina Aittomäki, Liene Nikitina-Zake, Manuel R. Teixeira, Edith Olah, Florentia Fostira, Beth N. Peshkin, Pierre Laurent-Puig, M. B. Terry, Michael T. Parsons, Anna González-Neira, Julie Lecarpentier, Jacek Gronwald, Fergus J. Couch, Mariarosaria Calvello, Leigha Senter, Ute Hamann, Brigitte Rack, Marco Montagna, Simon A. Gayther, Barbara Burwinkel, Anne-Vibeke Lænkholm, Irene L. Andrulis, Sabine Behrens, Beth Y. Karlan, Anthony J. Swerdlow, Marjanka K. Schmidt, Cari M. Kitahara, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Melissa A. Troester, Diana Torres, Daniel Barrowdale, Elinor J. Sawyer, Hiltrud Brauch, Minouk J. Schoemaker, Dale P. Sandler, José A. García-Sáenz, Jennifer Stone, Qin Wang, Conxi Lázaro, Paolo Radice, Jan Lubinski, Jose E. Castelao, Natalia Bogdanova, Drakoulis Yannoukakos, Davide Bondavalli, Kristan J. Aronson, Gad Rennert, Wing-Yee Lo, Robert N. Hoover, Dominique Stoppa-Lyonnet, Nadine Tung, Stephen J. Chanock, Andrew K. Godwin, Angela Cox, Maartje J. Hooning, Anthony Howell, Volker Arndt, Penny Soucy, Jenny Chang-Claude, Kathleen Claes, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Stig E. Bojesen, Sara Y Brucker, Darcy L. Thull, Darya Prokofyeva, Taru A. Muranen, Ben Schöttker, Orland Diez, Susan M. Gapstur, Sarah Sampson, Bernardo Bonanni, Per Hall, Ana Vega, Medical Oncology, Surgery, and Clinical Genetics
Subjects: Oncology, medicine.medical_specialty, Linkage disequilibrium, Carcinogenesis, Estrogen receptor, Genome-wide association study, Breast Neoplasms, Triple Negative Breast Neoplasms, Biology, Gene mutation, Linkage Disequilibrium, Càncer de mama, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Carcinogènesi, Triple-negative breast cancer, 030304 developmental biology, Medicinsk genetik, 0303 health sciences, Genetic heterogeneity, BRCA1 Protein, medicine.disease, 3. Good health, Case-Control Studies, Female, Mutation, Genome-Wide Association Study, Medical Genetics, 030217 neurology & neurosurgery
Abstract: Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020

10. Prediction and clinical utility of a contralateral breast cancer risk model

Author: William J. Tapper, Montserrat Garcia-Closas, Douglas F. Easton, Alison M. Dunning, Annika Lindblom, Rob A. E. M. Tollenaar, Hester S. A. Oldenburg, Per Hall, Chantal Van Ongeval, Diether Lambrechts, Daniele Giardiello, Agnes Jager, Jonine D. Figueroa, Melissa C. Southey, Qin Wang, Jan Lubinski, Ewout W. Steyerberg, Marjanka K. Schmidt, Manjeet K. Bolla, Anna Jakubowska, Paul D.P. Pharoah, Diana Eccles, Carl Blomqvist, Heli Nevanlinna, Flora E. van Leeuwen, Pieter J. Westenend, Mitul Shah, Iris Kramer, Luigi Mariani, Mehdi Manoochehri, Delal Akdeniz, Peter A. Fasching, Alexandra J. van den Broek, Muriel A. Adank, Saskia Pelders, Maartje J. Hooning, Christopher A. Haiman, Sabine Siesling, Loic Le Marchand, Peter Devilee, Michael Hauptmann, Ute Hamann, Jenny Chang-Claude, Camilla Wendt, Stig E. Bojesen, Lothar Haeberle, Mariël Brinkhuis, Laura J. van't Veer, Renske Keeman, Kamila Czene, Henrik Flyger, John L. Hopper, Audrey Y. Jung, Carolien H.M. van Deurzen, Vincent T.H.B.M. Smit, Health Technology & Services Research, Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Wang, Jean [0000-0002-9139-0627], Apollo - University of Cambridge Repository, Blomqvist, Carl [0000-0003-3041-1938], Department of Oncology, Clinicum, HUS Comprehensive Cancer Center, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, Public Health, Medical Oncology, and Pathology
Subjects: Oncology, medicine.medical_treatment, BRCA mutation carriers, 0302 clinical medicine, Medizinische Fakultät, 3123 Gynaecology and paediatrics, Risk Factors, 030212 general & internal medicine, Family history, 10. No inequality, Netherlands, education.field_of_study, BRCA1 Protein, Area under the curve, Disease Management, Neoplasms, Second Primary, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Primary tumor, 3. Good health, Preventive mastectomy, 030220 oncology & carcinogenesis, Area Under Curve, Female, Disease Susceptibility, Mastectomy, Clinical decision-making, Research Article, medicine.medical_specialty, Population, 3122 Cancers, Breast Neoplasms, Risk Assessment, lcsh:RC254-282, 03 medical and health sciences, Germline mutation, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, ddc:610, education, Germ-Line Mutation, Proportional Hazards Models, BRCA2 Protein, business.industry, medicine.disease, Contralateral breast cancer, business, Risk prediction model
Abstract: Background Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Methods We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.
Published: 2019

11. Health-Related Quality of Life in a Cohort of Breast Cancer Survivors over More Than 10 Years Post-Diagnosis and in Comparison to a Control Cohort

Author: Audrey Y. Jung, Kathrin Thöne, Sabine Behrens, Heiko Becher, Jenny Chang-Claude, Nadia Obi, and Tabea Maurer
Subjects: Cancer Research, Pediatrics, medicine.medical_specialty, longitudinal, Disease, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Quality of life, Survivorship curve, medicine, 030212 general & internal medicine, Risk factor, Cancer survivor, business.industry, Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, humanities, population-based, health-related quality of life, Oncology, 030220 oncology & carcinogenesis, Cohort, age effects, business, survivorship
Abstract: Simple Summary Breast cancer survivors often experience long-term side-effects of the disease and its treatment that negatively impact their quality of life. However, to date only few long-term studies on breast cancer survivor’s quality of life exist and it is unclear whether or not breast cancer survivors experience a worse quality of life than women without breast cancer. We therefore investigated breast cancer survivor’s quality of life before diagnosis, during active treatment as well as 5 and 10 years after diagnosis and compared it to the quality of life in women without breast cancer. We found that breast cancer survivor’s quality of life over all ages improved in the first 5 years and then started to deteriorate. After 10 years it was comparable to women without breast cancer. Yet, we showed that survivors of different ages experience differences in health related quality of life over time. Most importantly, we showed that 10 years after diagnosis younger patients reported a worse quality of life than women of the same age that never had breast cancer. These findings are important when trying to optimize long-term care of breast cancer survivors. Abstract Background: Breast cancer (BC) survivors often suffer from late and long-term residual symptoms of the disease and its treatment. To date, long-term health-related quality of life (HRQoL) in breast cancer survivors has been seldom investigated and rarely compared to unaffected women (controls). Aim: This study aimed to investigate HRQoL over time using patient-reported status before diagnosis, during treatment, 1 year post-surgery, approx. 5 years and ≥10 years post-diagnosis. We also compared survivors’ HRQoL with controls’ still alive 10 years after recruitment. Methods: Data from the German population-based Mamma Carcinoma Risk Factor Investigation (MARIE) cohort of 1123 BC patients aged 50–74 years at diagnosis (2002–2005) and of 3453 matched controls were used for analysis. HRQoL was assessed with the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) questionnaire. All analyses were conducted for all ages as well as stratified according to three age groups (≤58 years, 59–64 years, ≥64 years). Differences in survivors’ general HRQoL before, during, and after therapy were investigated using a t-test/Wilcoxon signed-rank test. Changes in the HRQoL of survivors stratified by age from FU1 to FU2 were assessed via repeated analysis of variance. The HRQoL of survivors compared to the controls at FU2 was analyzed using an analysis of variance. Results: Over all ages, the general HRQoL in patients improved in the first 5 years post-diagnosis. In the subsequent years, HRQoL slightly deteriorated but was comparable to that of the controls. Younger survivors mostly improved their HRQoL from the 5 to 10-year follow-up but remained negatively affected for most functioning and symptom scales compared to controls. In older survivors, HRQoL hardly changed over time and detriments were less pronounced compared to controls, except for insomnia. Conclusions: Restrictions of HRQoL persist for more than 10 years and are most prominent among younger survivors. Researchers and clinicians should be aware of such potential deteriorations and age-dependent differences in order to optimize/adapt long-term cancer survivor care.
Published: 2021

12. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Agnes Jager, Christopher A. Haiman, William G. Newman, Georgia Chenevix-Trench, Loic Le Marchand, Tjoung-Won Park-Simon, Eric Hahnen, Peter Kraft, Montserrat Garcia-Closas, Alison M. Dunning, Roger L. Milne, Christine L. Clarke, Wei He, Thomas Brüning, David J. Hunter, Alicja Wolk, Arto Mannermaa, William J. Tapper, Dimitrios Mavroudis, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Annelie Augustinsson, Rob A. E. M. Tollenaar, Stella Koutros, Heiko Becher, Machteld Keupers, Abctb Investigators, Esther M. John, Heli Nevanlinna, Simon S. Cross, Rita K. Schmutzler, Melanie Gündert, Elinor J. Sawyer, Anna Morra, Melissa C. Southey, Robert Luben, Daniele Campa, Hoda Anton-Culver, Hiltrud Brauch, Børge G. Nordestgaard, Wolfgang Janni, Douglas F. Easton, Diether Lambrechts, Marjanka K. Schmidt, Jonathan Beesley, Thilo Dörk, Miriam Dwek, Robert Winqvist, Irene L. Andrulis, Paolo Peterlongo, Manjeet K. Bolla, Manuela Gago-Dominguez, Matthias Ruebner, Nick Orr, Stephen J. Chanock, Paul L. Auer, Michael Lush, Sune F. Nielsen, Amber N Hurson, Alpa V. Patel, Sander Canisius, Vessela N. Kristensen, José A. García-Sáenz, Joe Dennis, Mervi Grip, Sarah Colonna, Tongguang Cheng, Martha S. Linet, Cari M. Kitahara, Annika Lindblom, Anna Jakubowska, Paul D.P. Pharoah, Bernard Peissel, Christopher G. Scott, Maria Elena Martinez, Laure Dossus, Saundra S. Buys, Graham G. Giles, Pascal Guénel, Anthony J. Swerdlow, Allison W. Kurian, Jan Lubinski, Andrew F. Olshan, A. Heather Eliassen, Valerie Rhenius, Jose E. Castelao, Renske Keeman, Diana Eccles, John W.M. Martens, Melissa A. Troester, Sara Margolin, Thomas U. Ahearn, Hedy S. Rennert, Nadege Presneau, Mehdi Manoochehri, Laura E. Beane Freeman, Lauren R. Teras, Jaana M. Hartikainen, Hermann Brenner, Reiner Hoppe, Atocha Romero, Mitul Shah, Peter A. Fasching, Argyrios Ziogas, Matthias W. Beckmann, Ross L. Prentice, James V. Lacey, Harald Surowy, Rulla M. Tamimi, D. Gareth Evans, Celine M. Vachon, Snezhana Smichkoska, Mary B. Daly, Karolina Prajzendanc, Arif B. Ekici, Stig E. Bojesen, Niclas Håkansson, Steven N. Hart, Mikael Eriksson, Maria Escala-Garcia, Taru A. Muranen, Arndt Hartmann, Henrik Flyger, Håkan Olsson, Federico Canzian, Rebecca Roylance, Mary Beth Terry, Jenny Chang-Claude, Andreas Schneeweiss, Angela Cox, Maartje J. Hooning, Anthony Howell, Volker Arndt, Lin Fritschi, Bette J. Caan, Kyriaki Michailidou, Per Hall, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Fergus J. Couch, Gad Rennert, Ute Hamann, Brigitte Rack, Sabine Behrens, Jennifer Stone, Qin Wang, kConFab Investigators, Kamila Czene, John L. Hopper, Audrey Y. Jung, Rudolf Kaaks, Schmidt, Marjanka K. [0000-0002-2228-429X], Apollo - University of Cambridge Repository, Dörk, Thilo [0000-0002-9458-0282], Newman, William G [0000-0002-6382-4678], Romero, Atocha [0000-0002-1634-7397], Stone, Jennifer [0000-0001-5077-0124], Schmidt, Marjanka K [0000-0002-2228-429X], HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and Medical Oncology
Subjects: Oncology, medicine.medical_treatment, LOCI, PROGRESSION, Systemic treatment, SUSCEPTIBILITY, BETA-CATENIN, Germline, SUBTYPES, 0302 clinical medicine, Surgical oncology, TOOL, Medicine, RC254-282, 0303 health sciences, Tumor biology, ROLES, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Single Nucleotide, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Female, Research Article, EXPRESSION, medicine.medical_specialty, 3122 Cancers, Breast Neoplasms, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Humans, ddc:610, Polymorphism, Allele, Breast cancer-specific survival, Common germline genetic variants, Patient subgroups, Genome-Wide Association Study, Survival Analysis, Germ-Line Mutation, Pathological, 030304 developmental biology, Cancer och onkologi, Chemotherapy, IDENTIFICATION, business.industry, Proportional hazards model, medicine.disease, Confidence interval, Cancer and Oncology, Breast Cancer-specific Survival, Common Germline Genetic Variants, Patient Subgroups, Systemic Treatment, Tumor Biology, business
Abstract: Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
Published: 2021

13. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Georgia Chenevix-Trench, Tjoung-Won Park-Simon, David J. Hunter, Lauren R. Teras, Harald Surowy, Rulla M. Tamimi, Jaana M. Hartikainen, Fergus J. Couch, Heli Nevanlinna, Celine M. Vachon, Per Hall, Arif B. Ekici, Vessela N. Kristensen, Ute Hamann, Alpa V. Patel, Christopher A. Haiman, Sander Canisius, Jonathan Beesley, Sara Margolin, Hedy S. Rennert, Thilo Dörk, Paolo Peterlongo, Hoda Anton-Culver, Matthias W. Beckmann, Renske Keeman, Christopher G. Scott, Rudolf Kaaks, Melissa C. Southey, Atocha Romero, Stig E. Bojesen, Graham G. Giles, Federico Canzian, Rebecca Roylance, Stephen J. Chanock, Loic Le Marchand, Eric Hahnen, Robert Winqvist, Mervi Grip, Taru A. Muranen, A. Heather Eliassen, Ian Tomlinson, Anna Jakubowska, Emilie Thomas, Douglas F. Easton, William Jacot, Paul D.P. Pharoah, Elinor J. Sawyer, Linetta B. Koppert, Manuela Gago-Dominguez, Anthony J. Swerdlow, Matthias Ruebner, Joe Dennis, Alison M. Dunning, Esther M. John, Elza Khusnutdinova, Melanie Gündert, Kamila Czene, Dimitrios Mavroudis, Henrik Flyger, Minouk J. Schoemaker, Manjeet K. Bolla, Rita K. Schmutzler, Jenny Chang-Claude, Kyriaki Michailidou, Håkan Olsson, John L. Hopper, Marjanka K. Schmidt, Melissa A. Troester, Audrey Y. Jung, Maria Escala-Garcia, Bernadette A M Heemskerk-Gerritsen, Argyrios Ziogas, Thomas Rüdiger, Antoinette Hollestelle, José A. García-Sáenz, Marina Bermisheva, Alicja Wolk, Volker Arndt, Robert N. Luben, Mary B. Daly, Niclas Håkansson, Jan Lubinski, Jose E. Castelao, Emmanouil Saloustros, Jürgen Geisler, Qin Wang, Paolo Radice, Gad Rennert, Thomas Bachelot, Sabine Behrens, Peter Kraft, Arto Mannermaa, Heiko Becher, Annika Lindblom, Annelie Augustinsson, Andrew F. Olshan, Mehdi Manoochehri, Peter A. Fasching, Allison W. Kurian, Hermann Brenner, Reiner Hoppe, Montserrat Garcia-Closas, Diether Lambrechts, Kevin Punie, Peter Devilee, Dörk, Thilo [0000-0002-9458-0282], Romero, Atocha [0000-0002-1634-7397], Apollo - University of Cambridge Repository, Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Medical Oncology, Surgery, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology
Subjects: Oncology, Kaplan-Meier Estimate, SUSCEPTIBILITY, Germline, Metastasis, Breast cancer, 0302 clinical medicine, Cancer Survivors, 3123 Gynaecology and paediatrics, NETWORK, skin and connective tissue diseases, Cancer genetics, 0303 health sciences, Multidisciplinary, article, WOMEN, Metastatic breast cancer, 3. Good health, Multidisciplinary Sciences, 631/67/322, 030220 oncology & carcinogenesis, Medicine, Science & Technology - Other Topics, Female, Primary breast cancer, medicine.medical_specialty, Science, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 631/67/68, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, In patient, Germ-Line Mutation, 030304 developmental biology, Cancer och onkologi, Science & Technology, business.industry, Genetic Variation, Breast cancer metastasis, 631/67/1347, medicine.disease, Germ Cells, Cancer and Oncology, business
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021

14. Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts

Author: Kamila Czene, John L. Hopper, Audrey Y. Jung, William J. Tapper, Sabine Siesling, Camilla Wendt, Daniele Giardiello, Stig E. Bojesen, Michael Hauptmann, Maartje J. Hooning, Pieter J. Westenend, Alison M. Dunning, Diana Eccles, Peter Devilee, Linetta B. Koppert, Delal Akdeniz, Henrik Flyger, Chantal Van Ongeval, Luigi Mariani, Mitul Shah, Saskia Pelders, Muriel A. Adank, Agnes Jager, Jan Lubinski, Melissa C. Southey, Manjeet K. Bolla, Flora E. van Leeuwen, Carl Blomqvist, Anna Jakubowska, Paul D.P. Pharoah, Jenny Chang-Claude, Douglas F. Easton, Laura J. van't Veer, Renske Keeman, Qin Wang, Alexandra J. van den Broek, Hester S. A. Oldenburg, Carolien H.M. van Deurzen, Lothar Haeberle, Per Hall, Rob A. E. M. Tollenaar, Mariël Brinkhuis, Jonine D. Figueroa, Ute Hamann, J. Blom, Montserrat Garcia-Closas, Mehdi Manoochehri, Peter A. Fasching, Diether Lambrechts, Ewout W. Steyerberg, Iris Kramer, Marjanka K. Schmidt, Vincent T.H.B.M. Smit, Christopher A. Haiman, Loic Le Marchand, Annika Lindblom, Heli Nevanlinna, Public Health, and Medical Oncology
Subjects: 0301 basic medicine, Cancer Research, IMPACT, Receptor, ErbB-2, Contralateral breast cancer, Cohort Studies, 0302 clinical medicine, Clinical decision making, Risk Factors, Validation, MUTATION, Mastectomy, CALIBRATION, education.field_of_study, Neoplasms, Second Primary, Prognosis, Risk prediction, 3. Good health, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, Clinical decision-making, Adult, medicine.medical_specialty, MODELS, Population, Breast Neoplasms, Risk Assessment, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, In patient, education, Science & Technology, business.industry, External validation, International Agencies, medicine.disease, Confidence interval, 030104 developmental biology, business, Follow-Up Studies
Abstract: BACKGROUND: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). METHODS: We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. RESULTS: The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. CONCLUSIONS: Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making. ispartof: BREAST CANCER RESEARCH AND TREATMENT vol:181 issue:2 pages:423-434 ispartof: location:Netherlands status: published
Published: 2020

15. Combined associations of a polygenic risk score and classical risk factors with breast cancer risk

Author: Diether Lambrechts, James Y. Dai, Pascal Guénel, Graham G. Giles, Montserrat Garcia-Closas, Javier Benitez, Thomas Brüning, Georgia Chenevix-Trench, Stig E. Bojesen, Rodney J Scott, Angela Cox, Anthony Howell, Nilanjan Chatterjee, Volker Arndt, Christopher J. Scott, Rudolf Kaaks, A. Heather Eliassen, Clarice R. Weinberg, Kyriaki Michailidou, Melissa C. Southey, Joe Dennis, Xiaoliang Wang, Niclas Håkansson, Anthony J Swerdlow, Laura E. Beane Freeman, Peter A. Fasching, David J. Hunter, Kristan J. Aronson, Jack A. Taylor, Thomas U. Ahearn, Håkan Olsson, Hoda Anton-Culver, Matthias W. Beckmann, Jenny Chang-Claude, Qiuyin Cai, Renske Keeman, Roger L. Milne, Bernd Holleczek, Jolanta Lissowska, Mia M. Gaudet, Paul D.P. Pharoah, Federico Canzian, Andrew F Olshan, Janet E. Olson, Susan M. Gapstur, Amber N Wilcox, John J. Spinelli, Christine L. Clarke, Stella Koutros, Ann Smeets, Brian D. Carter, Tabea Maurer, W Willett, Catriona McLean, Caroline Weltens, Hiltrud Brauch, Arif B. Ekici, Lin Fritschi, Maria Elena Martinez, Nick Orr, Dale P. Sandler, Yon-Dschun Ko, Simon S. Cross, Xiaohong R. Yang, Aaron D. Norman, Zomoroda Abu-Ful, Flavio Lejbkowicz, Per Hall, Allison W. Kurian, Ben Schöttker, Douglas F. Easton, Lothar Haeberle, Hermann Brenner, Manuela Gago-Dominguez, Robert J. MacInnis, Xiao-Ou Shu, Eunjung Lee, Martha S. Linet, kConFab, Aocs Investigators, Sigrid Hatse, Paul L. Auer, Christobel Saunders, Sara Lindström, Jonine D. Figueroa, Melissa A Troester, Parichoy Pal Choudhury, Ana Llaneza, Peter Kraft, Angel Carracedo, Christopher A. Haiman, Jose E. Castelao, Manjeet K. Bolla, Heiko Becher, Fredrick R. Schumacher, Alicia Beeghly-Fadiel, Hedy S. Rennert, Argyrios Ziogas, Charles M. Perou, Leslie Bernstein, Anna González-Neira, Irene L. Andrulis, H. Shelton Earp, Cari M. Kitahara, G Pita, Stacey J Winham, Wei Zheng, Pooja Middha Kapoor, Abctb Investigators, Kathryn J Ruddy, Minouk J. Schoemaker, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Chi Gao, Rulla M. Tamimi, Kamila Czene, D. Gareth Evans, John L. Hopper, Audrey Y. Jung, Loic Le Marchand, Michael Jones, Marike Gabrielson, Celine M. Vachon, Ross L. Prentice, Katie M. O'Brien, Esther M. John, Jennifer Stone, Daniele Campa, Elke M. van Veen, Qin Wang, Jane Heyworth, Alison M. Dunning, William G. Newman, Nasim Mavaddat, Marjanka K. Schmidt, Gad Rennert, Mikael Eriksson, Sabine Behrens, Susan L. Neuhausen, Stephen J. Chanock, Alicja Wolk, and Eric C Polley
Subjects: Cancer Research, Epidemiology, Gene-environment interactions, Logistic regression, Body Mass Index, 0302 clinical medicine, Breast cancer, Medicine, 10. No inequality, Medical History Taking, Estrogen Receptor Status, Aged, 80 and over, 0303 health sciences, Middle Aged, Risk prediction, 3. Good health, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, AcademicSubjects/MED00010, Medical Genetics, medicine.medical_specialty, Breast Neoplasms, Brief Communication, Polymorphism, Single Nucleotide, White People, Genetic susceptibility, Polygenic risk score, Risk factors, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Risk factor, Medicinsk genetik, 030304 developmental biology, Aged, Cancer och onkologi, business.industry, Case-control study, Cancer, Odds ratio, medicine.disease, Logistic Models, Cancer and Oncology, Case-Control Studies, business, Demography
Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer. ispartof: JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE vol:113 issue:3 pages:329-337 ispartof: location:United States status: published
Published: 2020

16. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Christine L. Clarke, Pierre Laurent-Puig, Mary B. Daly, Jacek Gronwald, Douglas F. Easton, M. B. Terry, Dominique Stoppa-Lyonnet, Mads Thomassen, Fergus J. Couch, José A. García-Sáenz, Mariarosaria Calvello, Florentia Fostira, Nadine Tung, Manuela Gago-Dominguez, Gad Rennert, Ute Hamann, Brigitte Rack, Csilla Szabo, Rudolf Kaaks, Kamila Czene, Simon A. Gayther, Sabine Behrens, John L. Hopper, kConFab Investigators, Barbara Burwinkel, Anne-Vibeke Lænkholm, Elaine F. Harkness, Audrey Y. Jung, János Papp, Usha Menon, Stephen J. Chanock, Lenka Foretova, Andrew K. Godwin, Snezhana Smichkoska, William J. Tapper, Melissa Christiaens, Muhammad Usman Rashid, Per Hall, Ana Vega, Elke M van Veen, Kathleen Claes, Pascal Guénel, Jennifer T. Loud, Roger L. Milne, Vessela N. Kristensen, Katarzyna Białkowska, Xia Jiang, Manuel R. Teixeira, Antoinette Hollestelle, Debra Frost, Noura Mebirouk, Beth N. Peshkin, Olufunmilayo I. Olopade, Bernd Holleczek, Andreas Schneeweiss, Hermann Brenner, Jeffrey N. Weitzel, Goska Leslie, Stig E. Bojesen, Peter J. Hulick, Xiaohong R. Yang, Mark S. Goldberg, Ignacio Briceño, Heli Nevanlinna, Maren T. Scheuner, Thilo Dörk, John J. Spinelli, Tracy A. O'Mara, Maria A. Caligo, Claire Mulot, Nick Orr, Anna González-Neira, Sara Y Brucker, Darcy L. Thull, Darya Prokofyeva, Paul L. Auer, Hans Wildiers, Jan Lubinski, Jose E. Castelao, Diana Eccles, Priyanka Sharma, Jonine D. Figueroa, Maria Elena Martinez, Wendy K. Chung, Rulla M. Tamimi, Taru A. Muranen, Wing-Yee Lo, Rob A. E. M. Tollenaar, Thomas Rüdiger, Natalia Bogdanova, Louise Izatt, Ben Schöttker, Thomas U. Ahearn, Hedy S. Rennert, Claudine Isaacs, Embrace Study, Jennifer Stone, Jolanta Lissowska, D. Gareth Evans, Matthias W. Beckmann, Peter Schürmann, Qin Wang, Orland Diez, Christopher R. Hake, Mehdi Manoochehri, Peter A. Fasching, Lesley McGuffog, Haoyu Zhang, Joe Dennis, Hanna Huebner, Judy Garber, Drakoulis Yannoukakos, Kenneth Offit, Yon-Dschun Ko, Celine M. Vachon, Robert N. Hoover, Marc Tischkowitz, Pooja Middha Kapoor, Agnes Jager, Davide Bondavalli, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Marjanka K. Schmidt, Edith Olah, Laura Papi, Conxi Lázaro, Arif B. Ekici, Paolo Radice, Austin Miller, Kristan J. Aronson, Harvey A. Risch, Jack A. Taylor, Robert Winqvist, Jacques Simard, Catriona McLean, Michael T. Parsons, Wei Zheng, Linetta B. Koppert, Susan M. Gapstur, Georgia Chenevix-Trench, Susan M. Domchek, Tjoung-Won Park-Simon, Zumuruda Abu Ful, Javier Benitez, Clarice R. Weinberg, Kyriaki Michailidou, Alfons Meindl, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Ana Blanco, Nilanjan Chatterjee, Montserrat Garcia-Closas, Thomas Brüning, Rita K. Schmutzler, Lizet E. van der Kolk, Peter Hillemanns, Beth Y. Karlan, Hoda Anton-Culver, Ans M.W. van den Ouweland, Banu Arun, J. Peto, Anthony J. Swerdlow, Marco Montagna, Ana Peixoto, Emmanouil Saloustros, Peter Kraft, Mark H. Greene, Evgeny N. Imyanitov, Siranoush Manoukian, Diether Lambrechts, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Milena Jakimovska, Dijana Plaseska-Karanfilska, Kristiina Aittomäki, Johanna Rantala, Kelly-Anne Phillips, Melissa A. Troester, Michael Untch, Susan J. Ramus, Arto Mannermaa, Christian F. Singer, Abctb Investigators, Bernard Peissel, Daniel Barrowdale, Elinor J. Sawyer, Jacopo Azzollini, Leigha Senter, Antonis C. Antoniou, Barbara Wappenschmidt, Hiltrud Brauch, Heiko Becher, Julie Lecarpentier, Sarah Sampson, Jonathan Beesley, Eitan Friedman, Dale P. Sandler, Minouk J. Schoemaker, Irene L. Andrulis, Paolo Peterlongo, Saundra S. Buys, Stella Koutros, Lothar Häberle, Christopher A. Haiman, Fabienne Lesueur, Cari M. Kitahara, Peter Devilee, Kristin K. Zorn, Karolina Prajzendanc, Monica Zuradelli, Simon S. Cross, William G. Newman, Ni Zhao, Jesse Nodora, Susanna C. Larsson, Helen Byers, Flavio Lejbkowicz, Trinidad Caldés, Eric Hahnen, Laura Matricardi, Daniel R. Barnes, Mark E. Sherman, Åke Borg, Angela Cox, Maartje J. Hooning, Anthony Howell, Volker Arndt, Diana Torres, Penny Soucy, Bernardo Bonanni, Ross L. Prentice, Marion Piedmonte, Xiao-Ou Shu, Elvira Mingazheva, Elza Khusnutdinova, Patrick Neven, Renske Keeman, Matti A. Rookus, Manjeet K. Bolla, Atocha Romero, Robert J. MacInnis, Jenny Chang-Claude, Irene Konstantopoulou, Emilija Lazarova, Annegien Broeks, Carl Blomqvist, Annika Lindblom, Bernadette A M Heemskerk-Gerritsen, Matthias Rübner, Graham G. Giles, Hans Christiansen, Liene Nikitina-Zake, Håkan Olsson, Wolfgang Janni, Sofia Khan, Katherine L. Nathanson, Alicja Lukomska, Miriam Dwek, Sara Margolin, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Elizabeth J. van Rensburg, Michael Jones, Frans B. L. Hogervorst, Esther M. John, Alison M. Dunning, Daniele Campa, Guanghao Qi, Sten Cornelissen, and Paul A. James
Subjects: 0303 health sciences, Estrogen receptor, Genome-wide association study, Biology, medicine.disease, Tumor heterogeneity, 3. Good health, Tumor Subtype, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Progesterone receptor, Susceptibility locus, medicine, Cancer research, Human Epidermal Growth Factor Receptor 2, 030304 developmental biology
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate PIn-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2019
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17. A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases

Author: Christine Chow, Hugh Luk, Jennifer Alsop, Aleksandra Tołoczko-Grabarek, Qin Wang, Nicola S. Meagher, Janusz Menkiszak, Stacey J. Winham, Jan Lubinski, Bonnie Zhang, Simon A. Gayther, Gary L. Keeney, Rhonda Farrell, Tomasz Kluz, Constantina Mateoiu, Mona El-Bahrawy, Raghwa Sharma, Montserrat Garcia-Closas, Adeline Tan, Brenda Y. Hernandez, Minouk J. Schoemaker, Maria P. Intermaggio, Marc T. Goodman, Robert A. Vierkant, Björg Kristjansdottir, Chloe Karpinskyj, Penny Coulson, Parham Minoo, Kylie L. Gorringe, Aline Talhouk, Oliver F. Bathe, Anthony J. Swerdlow, Michael E. Carney, James D. Brenton, Robert P. Edwards, John Lewis Etter, Kirsten B. Moysich, Colin J.R. Stewart, Jennifer M Koziak, Mercedes Jimenez-Linan, Yee Leung, Kunle Odunsi, Peter F Rambau, Sabine Behrens, Linda S. Cook, Michael S. Anglesio, Lynne R. Wilkens, Karin Sundfeldt, Esther Herpel, Martin Köbel, Sanela Bilic, Jacek Gronwald, Paul R. Harnett, Helen Steed, Katrina Tang, Susan J. Ramus, Paul A. Cohen, Xianyong Gui, Frances Daley, Ellen L. Goode, Anna deFazio, Ian G. Campbell, Paul D.P. Pharoah, Peter Sinn, Paul Klonowski, Yanina Natanzon, Linyuan Wang, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Catherine J. Kennedy, Roberta B. Ness, Linda E. Kelemen, Oleg Oszurek, Usha Menon, Mitul Shah, Martin Widschwendter, Melissa C. Larson, Gregory Robertson, Francesmary Modugno, David G. Huntsman, Audrey Y. Jung, and Neil Lambie
Subjects: 0301 basic medicine, Male, Pathology, 0302 clinical medicine, Medicine, Neoplasm Metastasis, 11 Medical and Health Sciences, Ovarian Neoplasms, Tissue microarray, SERIES, Adenocarcinoma, Mucinous, Immunohistochemistry, Appendiceal Neoplasms, 030220 oncology & carcinogenesis, Cohort, SURVIVAL, Adenocarcinoma, Female, Colorectal Neoplasms, Life Sciences & Biomedicine, NEOPLASMS, EXPRESSION, medicine.medical_specialty, CARCINOMA, CANCERS, Sensitivity and Specificity, Article, Pathology and Forensic Medicine, Diagnosis, Differential, 03 medical and health sciences, DISTINCTION, Carcinoma, Biomarkers, Tumor, Humans, Science & Technology, business.industry, Keratin-7, Histology, ADENOCARCINOMA, PROFILES, Matrix Attachment Region Binding Proteins, medicine.disease, 030104 developmental biology, CDX2, Keratin 7, business, PAX8, Transcription Factors
Abstract: Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.
Published: 2019

18. 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

19. Adherence to Cancer Prevention Guidelines among Older White and Black Adults in the Health ABC Study

Author: Hilsa N. Ayonayon, Anne B. Newman, Jane A. Cauley, Iva Miljkovic, Tamara B. Harris, Heidi D. Klepin, Rachel A. Murphy, Stephen B. Kritchevsky, Audrey Y. Jung, and Susan M. Rubin
Subjects: Male, medicine.medical_specialty, lifestyle, Younger age, Health Behavior, Population, lcsh:TX341-641, Disease, White People, Article, Body Mass Index, Older population, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, prevention, Risk Factors, Neoplasms, Surveys and Questionnaires, Activities of Daily Living, Humans, Medicine, Processed meat, Prospective Studies, 030212 general & internal medicine, education, Exercise, Life Style, Aged, education.field_of_study, Nutrition and Dietetics, Cancer prevention, business.industry, Public health, aging, Feeding Behavior, Diet, 3. Good health, Black or African American, nutrition, 030220 oncology & carcinogenesis, Cohort, Body Composition, Female, business, lcsh:Nutrition. Foods and food supply, Food Science, Demography
Abstract: One-third of cancers can be prevented through healthy lifestyles. This study investigates the prevalence of and factors associated with engagement in cancer prevention guidelines in a population-based cohort of 2124 older white and black men and women. We used Health ABC data to construct a score from 0 (lowest adherence) to 7 (greatest adherence) based on the sum of seven recommendations for cancer prevention from the World Cancer Research Fund/American Institute for Cancer Research, body fatness (maintenance of healthy body weight), physical activity (at least moderately physically active), diet (fruit, vegetables, fiber, and red and processed meat), and alcohol. Mean (SD) scores in men and women were 3.24 (1.09) and 3.17 (1.10). Lower scores were associated with younger age (women only), black race, current smoking, and prevalent cardiovascular disease. Less than 1% of men and women adhered to all recommendations. Of the individual guidelines, adherence was lowest for fiber (9% of men, 6% of women) followed by physical activity (26% of men, 18% of women), and body weight (21% of men, 26% of women). These results suggest a critical public health need, especially given the growing older population. Black older adults, smokers, and those with prevalent disease may be at higher risk and thus warrant additional focus.
Published: 2019

20. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Wing-Yee Lo, Dhanya Ramachandran, Christos Petridis, Fernando Salvador Moreno, Tongguang Cheng, Bernardo Bonanni, Ann Smeets, Susan E. Hankinson, Caroline Seynaeve, Suet-Feung Chin, Vessela N. Kristensen, Christopher G. Scott, Javier Benitez, William T. Newman, Brigitte Rack, Marjanka K. Schmidt, Diether Lambrechts, Alfons Meindl, Maria Escala-Garcia, Hoda Anton-Culver, Veli-Matti Kosma, Nadege Presneau, Daniel F. Schmidt, Douglas F. Easton, Ans M.W. van den Ouweland, Emmanouil Saloustros, Antoinette Hollestelle, Darya Prokofieva, Elinor J. Sawyer, Louise A. Brinton, Manuela Gago-Dominguez, Minouk J. Schoemaker, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Eva Galle, Catriona McLean, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Per Hall, Jaana M. Hartikainen, Leslie Bernstein, Jose Ignacio Arias Perez, Flavio Lejbkowicz, Qi Guo, Brian D. Carter, Martha S. Linet, Fredrick R. Schumacher, Yan Zhang, Mikael Eriksson, Hiltrud Brauch, Janet A. Dunn, Gord Glendon, Bernd Holleczek, William J. Tapper, Marike Gabrielson, Keith Humphreys, Rodney J. Scott, Tabea Kühl, Lorraine Durcan, David J. Hunter, Pascal Guénel, Tom Maishman, Mary B. Daly, Rami Nassir, Andreas Schneeweiss, Kamila Czene, Jonine D. Figueroa, Grethe I. Grenaker Alnæs, Julia A. Knight, Angel Carracedo, Susan M. Gapstur, Manuel R. Teixeira, Guanmengqian Huang, Paul L. Auer, Sara Y. Brucker, Johanna I. Kiiski, Adam R. Brentnall, Simon S. Cross, Joe Dennis, Nicola Miller, Walter C. Willett, Melissa C. Southey, Christoph Engel, Niclas Håkansson, Diana Eccles, John L. Hopper, Elaine F. Harkness, Audrey Y. Jung, Trinidad Caldés, Steven N. Hart, Sara Lindström, Michael P. Lux, Julie Lecarpentier, Lian Li, Robert Winqvist, Peter Kraft, Stephen J. Chanock, Thilo Dörk, Melanie Maierthaler, Rudolf Kaaks, Angela Cox, Maartje J. Hooning, José A. García-Sáenz, Christi J. van Asperen, Mervi Grip, Enes Makalic, Mia M. Gaudet, David E. Goldgar, Ross L. Prentice, Carolina Ellberg, Sune F. Nielsen, Federico Canzian, Rebecca Roylance, Aline Talhouk, Vassilios Georgoulias, Eunjung Lee, Siranoush Manoukian, Sara Margolin, Paul D.P. Pharoah, Hedy S. Rennert, Mitul Shah, Matthias W. Beckmann, Anthony Howell, Anne Lise Børresen-Dale, Christopher A. Haiman, V. Shane Pankratz, Anna González-Neira, Kathrin Thöne, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Ute Krüger, Mehdi Manoochehri, Arja Jukkola-Vuorinen, Loic Le Marchand, Katri Pylkäs, Peter Hillemanns, Dieter Flesch-Janys, Volker Arndt, Peter A. Fasching, Christine L. Clarke, Louise Hiller, Eric Hahnen, Jan Lubinski, Jose E. Castelao, Roger L. Milne, Linetta B. Koppert, Peter Devilee, Rob A. E. M. Tollenaar, Ian W. Brock, Claire Mulot, Mila Pinchev, Carlos Caldas, Michael Untch, Gadi Rennert, Aaron D. Norman, Per Broberg, Anthony J. Swerdlow, Lothar Haeberle, Heli Nevanlinna, Arto Mannermaa, Irene L. Andrulis, Angela George, Montserrat Garcia-Closas, Jolanta Lissowska, Jonathan Beesley, Paolo Peterlongo, Cari M. Kitahara, Rulla M. Tamimi, Annika Lindblom, Sabine Behrens, Nick Orr, David G. Cox, D. Gareth Evans, Jacques Simard, Diana Torres, Constance Turman, Celine M. Vachon, Qin Wang, Hans-Ulrich Ulmer, Maria Kabisch, Maria Elena Martinez, Paolo Radice, Maria Tengström, Dimitrios Mavroudis, Jean Abraham, Helena M. Earl, Alice S. Whittemore, Hermann Brenner, Rita K. Schmutzler, Børge G. Nordestgaard, Barbara Burwinkel, Michael Jones, Esther M. John, Patricia Harrington, Daniele Campa, Elke M. van Veen, Clara Pérez-Barrios, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Elza Khusnutdinova, Michael J. Kerin, Miriam Dwek, Sibylle Loibl, Manjeet K. Bolla, Carl Blomqvist, Sander Canisius, Graham G. Giles, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Emilie Cordina-Duverger, Arif B. Ekici, Yon-Dschun Ko, Pooja Middha, Alison M. Dunning, Katarzyna Kaczmarek, Bram Boeckx, Mary Beth Terry, Jenny Chang-Claude, Karoliona Prajzendanc, Renske Keeman, Camilla Wendt, Atocha Romero, Stig E. Bojesen, Robert J. MacInnis, Clare Turnbull, Lukas Schwentner, Xiaohong R. Yang, Henrik Flyger, Håkan Olsson, Wolfgang Janni, Sofia Khan, Clinicum, Department of Oncology, University of Helsinki, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, HUS Comprehensive Cancer Center, Medical Oncology, Surgery, and Clinical Genetics
Subjects: Oncology, Cancer Research, PROGNOSIS, Genome-wide association study, PATHWAY, Prognostic markers, Breast cancer, 0302 clinical medicine, Epidemiology of cancer, Cancer genetics, RISK, Hazard ratio, SINGLE-NUCLEOTIDE POLYMORPHISMS, GENETIC-VARIATION, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, SURVIVAL, TUMOR SUBTYPES, Female, Chromosomes, Human, Pair 7, EXPRESSION, medicine.medical_specialty, CLINICAL-OUTCOMES, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Article, White People, NBCS Collaborators, RC0254, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Proportional Hazards Models, business.industry, Proportional hazards model, Genetic Variation, Cancer, Bayes Theorem, medicine.disease, business, Genome-Wide Association Study
Abstract: Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
Published: 2019

21. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Author: Andreas du Bois, Douglas F. Easton, Aleksandra Gentry-Maharaj, Heli Nevanlinna, Fiona Bruinsma, Iwona K. Rzepecka, Anna H. Wu, Jenny Chang-Claude, Jolanta Lissowska, Natalia Antonenkova, Beata Spiewankiewicz, Christine Walsh, Louise A. Brinton, Xifeng Wu, Leon F.A.G. Massuger, Audrey Y. Jung, Nadeem Siddiqui, Jenny Lester, Evelyn Despierre, Rosalind Glasspool, Jacek Gronwald, Claus Høgdall, Ellen L. Goode, Liisa M. Pelttari, Edwin S. Iversen, Alice S. Whittemore, Lynne R. Wilkens, Lene Lundvall, Robert P. Edwards, Natalia Bogdanova, Camilla Krakstad, Kunle Odunsi, Diana Eccles, Katja K.H. Aben, Weiva Sieh, Diether Lambrechts, Simon A. Gayther, Thomas A. Sellers, Satoyo Hosono, Yin Ling Woo, Jolanta Kupryjanczyk, Matthias W. Beckmann, Bu-Tian Ji, Shashi Lele, Pamela J. Thompson, Nicolas Wentzensen, Kirsten B. Moysich, Alice W. Lee, Kathryn L. Terry, Ira Schwaab, Estrid Høgdall, Yurii B. Shvetsov, Francesmary Modugno, Liv Cecilie Vestrheim Thomsen, Elizabeth M. Poole, Xiao-Ou Shu, Michelle A.T. Hildebrandt, Joellen M. Schildkraut, Arif B. Ekici, Hoda Anton-Culver, Philipp Harter, Celeste Leigh Pearce, Kristine G. Wicklund, Georgia Chenevix-Trench, Ralf Bützow, Eva S. Schernhammer, Madalene Earp, Roberta B. Ness, Steven A. Narod, James Paul, Tanja Pejovic, Soo-Hwang Teo, Florian Heitz, Catherine M. Phelan, Stacey J. Winham, Beth Y. Karlan, Susanne K. Kjaer, Sandrina Lambrechts, Jan Lubinski, Irene Orlow, Peter A. Fasching, Valerie McGuire, Lotte Ansgaard Thomsen, Joseph H. Rothstein, Honglin Song, Melissa Kellar, Usha Menon, Alvaro N.A. Monteiro, Ian G. Campbell, Hannah P. Yang, Graham G. Giles, Harvey A. Risch, Shan Wang-Gohrke, Linda E. Kelemen, Andrew Berchuck, Dong Liang, Karen Lu, Elisa V. Bandera, Robert A. Vierkant, John R. McLaughlin, Peter Hillemanns, Alexander Hein, Julie M. Cunningham, Daniel W. Cramer, Yukie Bean, Clareann H. Bunker, Brooke L. Fridley, Jennifer A. Doherty, Mary Anne Rossing, Joe Dennis, Shelley S. Tworoger, Allan Jensen, Thilo Dörk, Douglas A. Levine, Wei Zheng, Yong-Bing Xiang, Matthias Dürst, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Lara E. Sucheston-Campbell, Boon Kiong Lim, Sara H. Olson, Angela Brooks-Wilson, Ingo B. Runnebaum, Zheng Li, Jenny B. Permuth, Roger L. Milne, Barry P. Rosen, Iain A. McNeish, Argyrios Ziogas, Hui Yi Lin, Sandra Orsulic, Nhu D. Le, Malcolm C. Pike, Linda S. Cook, Line Bjørge, Karen Carty, Cezary Cybulski, Ganna Chornokur, Jonathan Tyrer, Susan J. Ramus, Anne M. van Altena, Marc T. Goodman, Ignace Vergote, Ingvild L. Tangen, Department of Pathology, Clinicum, University of Helsinki, Department of Obstetrics and Gynecology, Medicum, Doctoral Programme in Biomedicine, Scott, Rodney John, Dennis, Joe [0000-0003-4591-1214], Bruinsma, Fiona [0000-0002-9356-2015], Cunningham, Julie M [0000-0002-8159-3025], Giles, Graham G [0000-0003-4946-9099], Jakubowska, Anna [0000-0002-5650-0501], Li, Zheng [0000-0002-6141-4990], Sellers, Thomas A [0000-0002-7832-0405], Pharoah, Paul DP [0000-0001-8494-732X], Goode, Ellen L [0000-0002-9094-8326], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Hydrolases, Cell Membranes, Gene Expression, A Kinase Anchor Proteins, lcsh:Medicine, Genome-wide association study, GTPase, Carcinoma, Ovarian Epithelial, Biochemistry, Signaling Molecules, Cell Signaling, Risk Factors, 3123 Gynaecology and paediatrics, Medizinische Fakultät, GTPase Gene, Medicine and Health Sciences, Guanine Nucleotide Exchange Factors, Small GTPase, lcsh:Science, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Invasive Tumors, Genomics, A Kinase Anchor Proteins/genetics, Polymorphism, Single Nucleotide/genetics, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Enzymes, Multidisciplinary Sciences, Carcinoma, Ovarian Epithelial/genetics, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Science & Technology - Other Topics, Female, Guanine nucleotide exchange factor, Cellular Structures and Organelles, Anatomy, TRAITS, Research Article, Signal Transduction, Histology, Genotype, CARCINOMA, General Science & Technology, Rho GTPase-Activating Protein 5, Quantitative Trait Loci, 3122 Cancers, Ras Signaling, Biology, Polymorphism, Single Nucleotide, Monomeric GTP-Binding Proteins/genetics, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, GTP-binding protein regulators, MD Multidisciplinary, Genome-Wide Association Studies, Genetics, Humans, Gene Regulation, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, Rho Guanine Nucleotide Exchange Factors/genetics, Genetic Association Studies, Monomeric GTP-Binding Proteins, Science & Technology, lcsh:R, Biology and Life Sciences, Proteins, Membrane Proteins, Computational Biology, Cancers and Neoplasms, Human Genetics, Cell Biology, Genome Analysis, SUPER-ENHANCERS, Guanosine Triphosphatase, 030104 developmental biology, Cancer research, Enzymology, lcsh:Q, 3111 Biomedicine, Ras superfamily, Quantitative Trait Loci/genetics, Rho Guanine Nucleotide Exchange Factors
Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations. ispartof: PLOS ONE vol:13 issue:7 ispartof: location:United States status: published
Published: 2018

22. Dose-Response Relationship of CD8+ Tumor Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Author: Valerie McGuire, Mercedes Jimenez-Linan, Usha Menon, Anna deFazio, Ana Osorio, Joseph L. Kelley, Robert P. Edwards, Martin Köbel, Ian G. Campbell, Jennifer Alsop, Brooke L. Fridley, Beth Y. Karlan, Florin Andrei Taran, Susan J. Ramus, Javier Benitez, Luis Robles-Díaz, Linda E. Kelemen, Annette Staebler, Bryan M. McCauley, Arndt Hartmann, Paul R. Harnett, Janusz Menkiszak, Joseph H. Rothstein, Christiani Bisinoto de Sousa, Linda S. Cook, Oleg Oszurek, Raghwa Sharma, Naveena Singh, Jenny Lester, Matthew S. Block, Philipp Wagner, Matthias Ruebner, Andy Ryan, Jesús García-Donas, Martin Widschwendter, Helen Steed, Teri A. Longacre, Blake Gilks, Suha Deen, Jill Nation, Yanina Natanzon, Weiva Sieh, Marc T. Goodman, Daniel Guimarães Tiezzi, Maria P. Intermaggio, Chloe Karpinskyj, Anita Chudecka-Głaz, Maria J. Garcia, Chen Wang, Susanne K. Kjaer, Jillian Hung, Estrid Høgdall, Peter A. Fasching, Georgia Chenevix-Trench, Alexander Hein, Prafull Ghatage, A. Toloczko, Peter F Rambau, Catherine J. Kennedy, Aleksandra Gentry-Maharaj, Stacey J. Winham, Kimberly R. Kalli, Allan Jensen, Roberta B. Ness, Audrey Y. Jung, Jurandyr Moreira de Andrade, Wenqian Chen, Matthias W. Beckmann, Gregg Nelson, Jenny Chang-Claude, Jan Lubinski, Jennifer M Koziak, Paul D.P. Pharoah, Brenda Y. Hernandez, Jacek Gronwald, José Palacios, Alice S. Whittemore, Andreas D. Hartkopf, Sandra Orsulic, David L. Wachter, Sara Y. Brucker, Francesmary Modugno, Aliecia L. Bouligny, Peter Sinn, David G. Huntsman, Robert A. Vierkant, Zachary C. Fogarty, David D.L. Bowtell, James D. Brenton, Ursula Eilber, Ellen L. Goode, Stefan Kommoss, Kirsten B. Moysich, Sharon E. Johnatty, Anthony M. Magliocco, Francisco José Candido dos Reis, Bo Gao, Zheng Li, and Esther Herpel
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, CD8 Antigens, chemical and pharmacologic phenomena, Carcinoma, Ovarian Epithelial, Article, Cohort Studies, 03 medical and health sciences, Ovarian tumor, 0302 clinical medicine, Breast cancer, Lymphocytes, Tumor-Infiltrating, Internal medicine, Medicine, Humans, Prospective Studies, Prospective cohort study, Survival analysis, BRCA2 Protein, Ovarian Neoplasms, business.industry, Tumor-infiltrating lymphocytes, hemic and immune systems, Middle Aged, Debulking, medicine.disease, Survival Analysis, Cystadenocarcinoma, Serous, Serous fluid, 030104 developmental biology, Treatment Outcome, CITOTOXICIDADE IMUNOLÓGICA, 030220 oncology & carcinogenesis, Mutation, Female, Neoplasm Grading, business, Ovarian cancer
Abstract: Importance Cytotoxic CD8+tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+TILs in epithelial ovarian cancer. Design, Setting, and Participants This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures Following immunohistochemical analysis, CD8+TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures Overall survival time. Results The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+TILs, respectively (Pvalue for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germlineBRCA1pathogenic mutation, but were not prognostic forBRCA2mutation carriers. Evaluation of uncategorized CD8+TIL counts showed a near-log-linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.
Published: 2017

23. Dietary Supplement Use and Colorectal Adenoma Risk in Individuals with Lynch Syndrome: The GEOLynch Cohort Study

Author: Renate M. Winkels, Ellen Kampman, Akke Botma, Audrey Y. Jung, Fränzel J.B. Van Duijnhoven, Hans F. A. Vasen, Jan H. Kleibeuker, Fokko M. Nagengast, and Renate C. Heine-Bröring
Subjects: medicine.medical_specialty, Multidisciplinary, business.industry, Science, Dietary supplement, lcsh:R, Correction, lcsh:Medicine, Colorectal adenoma, medicine.disease, Lynch syndrome, Annotation, Internal medicine, medicine, Medicine, lcsh:Q, business, lcsh:Science, Cohort study
Published: 2014

24. Association of circulating leptin, adiponectin, and resistin concentrations with long-term breast cancer prognosis in a German patient cohort

Author: Nadia Obi, Audrey Y. Jung, Tabea Maurer, Marianne Huebner, Theron Johnson, Sabine Behrens, Stefanie Jaskulski, Heiko Becher, and Jenny Chang-Claude
Subjects: Medicine, Science
Abstract: Abstract Adipokines including leptin, adiponectin and resistin have been linked to risk of obesity-related cancers potentially through low-grade chronic inflammation pathways. We aimed to assess the role of post-diagnosis circulating adipokines on long-term prognosis in a prospective breast cancer cohort. Adipokines were measured in blood collected at baseline shortly after diagnosis (2002–2005) and at follow-up (2009) from 3112 breast cancer patients enrolled in the population-based MARIE study. Half of the patients had measurements at both time-points. All-cause mortality, breast cancer specific mortality and recurrences were ascertained up to June 2015 (11 years median follow-up). Associations with time-varying adipokine concentrations overall and stratified by estrogen and progesterone receptor (ERPR) were evaluated using adjusted proportional hazard regression. At baseline (n = 2700) and follow-up (n = 2027), median concentrations for leptin, adiponectin and resistin were 4.6 and 2.7 ng/ml, 24.4 and 30.0 mg/l, 15.4 and 26.2 ng/ml, respectively. After adjustment, there was no evidence for associations between adipokines and any outcome overall. In ERPR negative tumors, highest vs. lowest quintile of adiponectin was significantly associated with increased breast cancer specific mortality (HR 2.51, 95%CI 1.07–5.92). Overall, post-diagnosis adipokines were not associated with long-term outcomes after breast cancer. In patients with ERPR negative tumors, higher concentrations of adiponectin may be associated with increased breast cancer specific mortality and warrant further investigation.
Published: 2021
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25. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Maria Escala-Garcia, Sander Canisius, Renske Keeman, Jonathan Beesley, Hoda Anton-Culver, Volker Arndt, Annelie Augustinsson, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Fergus J. Couch, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M. Dunning, Douglas F. Easton, Arif B. Ekici, A. Heather Eliassen, Peter A. Fasching, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, José A. García-Sáenz, Jürgen Geisler, Graham G. Giles, Mervi Grip, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Jaana M. Hartikainen, Bernadette A. M. Heemskerk-Gerritsen, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, David J. Hunter, William Jacot, Anna Jakubowska, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Elza Khusnutdinova, Linetta B. Koppert, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Robert N. Luben, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Dimitrios Mavroudis, Taru A. Muranen, Heli Nevanlinna, Andrew F. Olshan, Håkan Olsson, Tjoung-Won Park-Simon, Alpa V. Patel, Paolo Peterlongo, Paul D. P. Pharoah, Kevin Punie, Paolo Radice, Gad Rennert, Hedy S. Rennert, Atocha Romero, Rebecca Roylance, Thomas Rüdiger, Matthias Ruebner, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Minouk J. Schoemaker, Christopher Scott, Melissa C. Southey, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, Lauren R. Teras, Emilie Thomas, Ian Tomlinson, Melissa A. Troester, Celine M. Vachon, Qin Wang, Robert Winqvist, Alicja Wolk, Argyrios Ziogas, kConFab/AOCS Investigators, Kyriaki Michailidou, Georgia Chenevix-Trench, Thomas Bachelot, and Marjanka K. Schmidt
Subjects: Medicine, Science
Abstract: Abstract Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021
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26. Adherence to Cancer Prevention Guidelines among Older White and Black Adults in the Health ABC Study

Author: Audrey Y. Jung, Iva Miljkovic, Susan Rubin, Stephen B. Kritchevsky, Heidi D. Klepin, Anne B. Newman, Jane Cauley, Hilsa Ayonayon, Tamara B. Harris, and Rachel A. Murphy
Subjects: lifestyle, nutrition, prevention, aging, Nutrition. Foods and food supply, TX341-641
Abstract: One-third of cancers can be prevented through healthy lifestyles. This study investigates the prevalence of and factors associated with engagement in cancer prevention guidelines in a population-based cohort of 2124 older white and black men and women. We used Health ABC data to construct a score from 0 (lowest adherence) to 7 (greatest adherence) based on the sum of seven recommendations for cancer prevention from the World Cancer Research Fund/American Institute for Cancer Research; body fatness (maintenance of healthy body weight), physical activity (at least moderately physically active), diet (fruit, vegetables, fiber, and red and processed meat), and alcohol. Mean (SD) scores in men and women were 3.24 (1.09) and 3.17 (1.10). Lower scores were associated with younger age (women only), black race, current smoking, and prevalent cardiovascular disease. Less than 1% of men and women adhered to all recommendations. Of the individual guidelines, adherence was lowest for fiber (9% of men; 6% of women) followed by physical activity (26% of men; 18% of women), and body weight (21% of men; 26% of women). These results suggest a critical public health need, especially given the growing older population. Black older adults, smokers, and those with prevalent disease may be at higher risk and thus warrant additional focus.
Published: 2019
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27. Correction: Dietary Supplement Use and Colorectal Adenoma Risk in Individuals with Lynch Syndrome: The GEOLynch Cohort Study.

Author: Renate C. Heine-Bröring, Renate M. Winkels, Akke Botma, Fränzel J. B. van Duijnhoven, Audrey Y. Jung, Jan H. Kleibeuker, Fokko M. Nagengast, Hans F. A. Vasen, and Ellen Kampman
Subjects: Medicine, Science
Published: 2014
Full Text: View/download PDF

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27 results on '"Audrey Y Jung"'

1. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

2. Dietary Supplement Use and Colorectal Adenoma Risk in Individuals with Lynch Syndrome: The GEOLynch Cohort Study.

3. No effect of folic acid supplementation on global DNA methylation in men and women with moderately elevated homocysteine.

4. Postdiagnosis circulating osteoprotegerin and TRAIL concentrations and survival and recurrence after a breast cancer diagnosis: results from the MARIE patient cohort

5. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

6. Pre- to postdiagnosis leisure-time physical activity and prognosis in postmenopausal breast cancer survivors

7. The impact of coding germline variants on contralateral breast cancer risk and survival

8. Breast cancer risk factors and survival by tumor subtype

9. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

10. Prediction and clinical utility of a contralateral breast cancer risk model

11. Health-Related Quality of Life in a Cohort of Breast Cancer Survivors over More Than 10 Years Post-Diagnosis and in Comparison to a Control Cohort

12. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

13. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

14. Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts

15. Combined associations of a polygenic risk score and classical risk factors with breast cancer risk

16. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

17. A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases

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

19. Adherence to Cancer Prevention Guidelines among Older White and Black Adults in the Health ABC Study

20. Genome-wide association study of germline variants and breast cancer-specific mortality

21. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

22. Dose-Response Relationship of CD8+ Tumor Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

23. Dietary Supplement Use and Colorectal Adenoma Risk in Individuals with Lynch Syndrome: The GEOLynch Cohort Study

24. Association of circulating leptin, adiponectin, and resistin concentrations with long-term breast cancer prognosis in a German patient cohort

25. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

26. Adherence to Cancer Prevention Guidelines among Older White and Black Adults in the Health ABC Study

27. Correction: Dietary Supplement Use and Colorectal Adenoma Risk in Individuals with Lynch Syndrome: The GEOLynch Cohort Study.

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