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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population
Nature Genetics. 2010 Oct;42(10) :885-+
PMID: ISI:000282276600020    PMCID: PMC3130795   
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Abstract
Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).
Notes
Antoniou, Antonis C. Wang, Xianshu Fredericksen, Zachary S. McGuffog, Lesley Tarrell, Robert Sinilnikova, Olga M. Healey, Sue Morrison, Jonathan Kartsonaki, Christiana Lesnick, Timothy Ghoussaini, Maya Barrowdale, Daniel Peock, Susan Cook, Margaret Oliver, Clare Frost, Debra Eccles, Diana Evans, D. Gareth Eeles, Ros Izatt, Louise Chu, Carol Douglas, Fiona Paterson, Joan Stoppa-Lyonnet, Dominique Houdayer, Claude Mazoyer, Sylvie Giraud, Sophie Lasset, Christine Remenieras, Audrey Caron, Olivier Hardouin, Agnes Berthet, Pascaline Hogervorst, Frans B. L. Rookus, Matti A. Jager, Agnes van den Ouweland, Ans Hoogerbrugge, Nicoline van der Luijt, Rob B. Meijers-Heijboer, Hanne Garcia, Encarna B. Gomez Devilee, Peter Vreeswijk, Maaike P. G. Lubinski, Jan Jakubowska, Anna Gronwald, Jacek Huzarski, Tomasz Byrski, Tomasz Gorski, Bohdan Cybulski, Cezary Spurdle, Amanda B. Holland, Helene Goldgar, David E. John, Esther M. Hopper, John L. Southey, Melissa Buys, Saundra S. Daly, Mary B. Terry, Mary-Beth Schmutzler, Rita K. Wappenschmidt, Barbara Engel, Christoph Meindl, Alfons Preisler-Adams, Sabine Arnold, Norbert Niederacher, Dieter Sutter, Christian Domchek, Susan M. Nathanson, Katherine L. Rebbeck, Timothy Blum, Joanne L. Piedmonte, Marion Rodriguez, Gustavo C. Wakeley, Katie Boggess, John F. Basil, Jack Blank, Stephanie V. Friedman, Eitan Kaufman, Bella Laitman, Yael Milgrom, Roni Andrulis, Irene L. Glendon, Gord Ozcelik, Hilmi Kirchhoff, Tomas Vijai, Joseph Gaudet, Mia M. Altshuler, David Guiducci, Candace Loman, Niklas Harbst, Katja Rantala, Johanna Ehrencrona, Hans Gerdes, Anne-Marie Thomassen, Mads Sunde, Lone Peterlongo, Paolo Manoukian, Siranoush Bonanni, Bernardo Viel, Alessandra Radice, Paolo Caldes, Trinidad de la Hoya, Miguel Singer, Christian F. Fink-Retter, Anneliese Greene, Mark H. Mai, Phuong L. Loud, Jennifer T. Guidugli, Lucia Lindor, Noralane M. Hansen, Thomas V. O. Nielsen, Finn C. Blanco, Ignacio Lazaro, Conxi Garber, Judy Ramus, Susan J. Gayther, Simon A. Phelan, Catherine Narod, Stephen Szabo, Csilla I. Benitez, Javier Osorio, Ana Nevanlinna, Heli Heikkinen, Tuomas Caligo, Maria A. Beattie, Mary S. Hamann, Ute Godwin, Andrew K. Montagna, Marco Casella, Cinzia Neuhausen, Susan L. Karlan, Beth Y. Tung, Nadine Toland, Amanda E. Weitzel, Jeffrey Olopade, Olofunmilayo Simard, Jacques Soucy, Penny Rubinstein, Wendy S. Arason, Adalgeir Rennert, Gad Martin, Nicholas G. Montgomery, Grant W. Chang-Claude, Jenny Flesch-Janys, Dieter Brauch, Hiltrud Severi, Gianluca Baglietto, Laura Cox, Angela Cross, Simon S. Miron, Penelope Gerty, Sue M. Tapper, William Yannoukakos, Drakoulis Fountzilas, George Fasching, Peter A. Beckmann, Matthias W. Silva, Isabel dos Santos Peto, Julian Lambrechts, Diether Paridaens, Robert Ruediger, Thomas Foersti, Asta Winqvist, Robert Pylkaes, Katri Diasio, Robert B. Lee, Adam M. Eckel-Passow, Jeanette Vachon, Celine Blows, Fiona Driver, Kristy Dunning, Alison Pharoah, Paul P. D. Offit, Kenneth Pankratz, V. Shane Hakonarson, Hakon Chenevix-Trench, Georgia Easton, Douglas F. Couch, Fergus J. Breast Cancer Research Foundation (BCRF) ; US National Institutes of Health [CA128978]; Cancer Research UK Financial support for this study was provided by the Breast Cancer Research Foundation (BCRF), Susan G. Komen for the Cure and US National Institutes of Health grant CA128978 to F. J. C. and by Cancer Research UK to D. F. E. and A. C. A. A. C. A. is a Cancer Research UK Senior Cancer Research Fellow and D. F. E. is a Cancer Research UK Principal Research Fellow. The authors thank Cancer Genetic Markers of Susceptability (CGEMS) and Wellcome Trust Case Control Consortium (WTCCC) for provision of genotype data from controls. Study specific acknowledgments listed in Supplementary Note. 32 Nature publishing group; 75 varick st, 9th flr, new york, ny 10013-1917 usa 655uo