Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers: Implications for Risk Prediction
Authors: Antonis C. Antoniou, Jonathan Beesley, Lesley McGuffog, Olga M. Sinilnikova, Sue Healey, Susan L. Neuhausen, Yuan Chun Ding, Timothy R. Rebbeck, Jeffrey N. Weitzel, Henry T. Lynch, Claudine Isaacs, Patricia A. Ganz, Gail Tomlinson, Olufunmilayo I. Olopade, Fergus J. Couch, Xianshu Wang, Noralane M. Lindor, Vernon S. Pankratz, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Monica Barile, Alessandra Viel, Anna Allavena, Valentina Dall'Olio, Paolo Peterlongo, Csilla I. Szabo, Michal Zikan, Kathleen Claes, Bruce Poppe, Lenka Foretova, Phuong L. Mai, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Gord Glendon, Hilmi Ozcelik, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Lone Sunde, Dorthe Cruger, Uffe Birk Jensen, Maria Caligo, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Maya Dubrovsky, Shimrit Cohen, Ake Borg, Helena Jernström, Annika Lindblom, Johanna Rantala, Marie Stenmark-Askmalm, Beatrice Melin, Kate Nathanson, Susan Domchek, Ania Jakubowska, Jan Lubinski, Tomasz Huzarski, Ana Osorio, Adriana Lasa, Mercedes Durán, Maria-Isabel Tejada, Javier Godino, Javier Benitez, Ute Hamann, Mieke Kriege, Nicoline Hoogerbrugge, Rob B. van der Luijt, Christi J. van Asperen, Peter Devilee, E.J. Meijers-Heijboer, Marinus J. Blok, Cora M. Aalfs, Frans Hogervorst, Matti Rookus, Margaret Cook, Clare Oliver, Debra Frost, Don Conroy, D. Gareth Evans, Fiona Lalloo, Gabriella Pichert, Rosemarie Davidson, Trevor Cole, Jackie Cook, Joan Paterson, Shirley Hodgson, Patrick J. Morrison, Mary E. Porteous, Lisa Walker, M. John Kennedy, Huw Dorkins, Susan Peock, Andrew K. Godwin, Dominique Stoppa-Lyonnet, Antoine de Pauw, Sylvie Mazoyer, Valérie Bonadona, Christine Lasset, Hélène Dreyfus, Dominique Leroux, Agnès Hardouin, Pascaline Berthet, Laurence Faivre, Catherine Loustalot, Tetsuro Noguchi, Hagay Sobol, Etienne Rouleau, Catherine Nogues, Marc Frénay, Laurence Vénat-Bouvet, John L. Hopper, Mary B. Daly, Mary B. Terry, Esther M. John, Saundra S. Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F. Singer, Anne Catharina Dressler, Daphne Gschwantler-Kaulich, Georg Pfeiler, Thomas V.O. Hansen, Lars Jønson, Bjarni A. Agnarsson, Tomas Kirchhoff, Kenneth Offit, Vincent Devlin, Ana Dutra-Clarke, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Peter E. Schwartz, Stephanie V. Blank, Amanda Ewart Toland, Marco Montagna, Cinzia Casella, Evgeny Imyanitov, Laima Tihomirova, Ignacio Blanco, Conxi Lazaro, Susan J. Ramus, Lara Sucheston, Beth Y. Karlan, Jenny Gross, Rita Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Magdalena Lochmann, Norbert Arnold, Simone Heidemann, Raymonda Varon-Mateeva, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Sabine Preisler-Adams, Karin Kast, Ines Schönbuchner, Trinidad Caldes, Miguel de la Hoya, Kristiina Aittomäki, Heli Nevanlinna, Jacques Simard, Amanda B. Spurdle, Helene Holland, Xiaoqing Chen, Radka Platte, Georgia Chenevix-Trench, Douglas F. Easton
Journal: Cancer Research (2010)

Abstract The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.