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Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction
Cancer Research. 2010 Dec;70(23) :9742-9754
PMCID: PMC2999830   
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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 x (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%
Notes
Antoniou, Antonis C. Beesley, Jonathan McGuffog, Lesley Sinilnikova, Olga M. Healey, Sue Neuhausen, Susan L. Ding, Yuan Chun Rebbeck, Timothy R. Weitzel, Jeffrey N. Lynch, Henry T. Isaacs, Claudine Ganz, Patricia A. Tomlinson, Gail Olopade, Olufunmilayo I. Couch, Fergus J. Wang, Xianshu Lindor, Noralane M. Pankratz, Vernon S. Radice, Paolo Manoukian, Siranoush Peissel, Bernard Zaffaroni, Daniela Barile, Monica Viel, Alessandra Allavena, Anna Dall'Olio, Valentina Peterlongo, Paolo Szabo, Csilla I. Zikan, Michal Claes, Kathleen Poppe, Bruce Foretova, Lenka Mai, Phuong L. Greene, Mark H. Rennert, Gad Lejbkowicz, Flavio Glendon, Gord Ozcelik, Hilmi Andrulis, Irene L. Thomassen, Mads Gerdes, Anne-Marie Sunde, Lone Cruger, Dorthe Jensen, Uffe Birk Caligo, Maria Friedman, Eitan Kaufman, Bella Laitman, Yael Milgrom, Roni Dubrovsky, Maya Cohen, Shimrit Borg, Ake Jernstroem, Helena Lindblom, Annika Rantala, Johanna Stenmark-Askmalm, Marie Melin, Beatrice Nathanson, Kate Domchek, Susan Jakubowska, Ania Lubinski, Jan Huzarski, Tomasz Osorio, Ana Lasa, Adriana Duran, Mercedes Tejada, Maria-Isabel Godino, Javier Benitez, Javier Hamann, Ute Kriege, Mieke Hoogerbrugge, Nicoline van der Luijt, Rob B. van Asperen, Christi J. Devilee, Peter Meijers-Heijboer, E. J. Blok, Marinus J. Aalfs, Cora M. Hogervorst, Frans Rookus, Matti Cook, Margaret Oliver, Clare Frost, Debra Conroy, Don Evans, D. Gareth Lalloo, Fiona Pichert, Gabriella Davidson, Rosemarie Cole, Trevor Cook, Jackie Paterson, Joan Hodgson, Shirley Morrison, Patrick J. Porteous, Mary E. Walker, Lisa Kennedy, M. John Dorkins, Huw Peock, Susan Godwin, Andrew K. Stoppa-Lyonnet, Dominique de Pauw, Antoine Mazoyer, Sylvie Bonadona, Valerie Lasset, Christine Dreyfus, Helene Leroux, Dominique Hardouin, Agnes Berthet, Pascaline Faivre, Laurence Loustalot, Catherine Noguchi, Tetsuro Sobol, Hagay Rouleau, Etienne Nogues, Catherine Frenay, Marc Venat-Bouvet, Laurence Hopper, John L. Daly, Mary B. Terry, Mary B. John, Esther M. Buys, Saundra S. Yassin, Yosuf Miron, Alexander Goldgar, David Singer, Christian F. Dressler, Anne Catharina Gschwantler-Kaulich, Daphne Pfeiler, Georg Hansen, Thomas V. O. Jnson, Lars Agnarsson, Bjarni A. Kirchhoff, Tomas Offit, Kenneth Devlin, Vincent Dutra-Clarke, Ana Piedmonte, Marion Rodriguez, Gustavo C. Wakeley, Katie Boggess, John F. Basil, Jack Schwartz, Peter E. Blank, Stephanie V. Toland, Amanda Ewart Montagna, Marco Casella, Cinzia Imyanitov, Evgeny Tihomirova, Laima Blanco, Ignacio Lazaro, Conxi Ramus, Susan J. Sucheston, Lara Karlan, Beth Y. Gross, Jenny Schmutzler, Rita Wappenschmidt, Barbara Engel, Christoph Meindl, Alfons Lochmann, Magdalena Arnold, Norbert Heidemann, Simone Varon-Mateeva, Raymonda Niederacher, Dieter Sutter, Christian Deissler, Helmut Gadzicki, Dorothea Preisler-Adams, Sabine Kast, Karin Schoenbuchner, Ines Caldes, Trinidad de la Hoya, Miguel Aittomaeki, Kristiina Nevanlinna, Heli Simard, Jacques Spurdle, Amanda B. Holland, Helene Chen, Xiaoqing Platte, Radka Chenevix-Trench, Georgia Easton, Douglas F. Amer assoc cancer research Philadelphia 690yj