Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction
Authors: 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 , Birk Jensen Uffe , Caligo Maria , Friedman Eitan , Kaufman Bella , Laitman Yael , Milgrom Roni , Dubrovsky Maya , Cohen Shimrit , Borg Ake , Jernström Helena , Lindblom Annika , Rantala Johanna , Stenmark-Askmalm Marie , Melin Beatrice , Nathanson Kate , Domchek Susan , Jakubowska Ania , Lubinski Jan , Huzarski Tomasz , Osorio Ana , Lasa Adriana , Durán Mercedes , Tejada Maria-Isabel , Godino Javier , Benitez Javier , Hamann Ute , Kriege Mieke , Hoogerbrugge Nicoline , van der Luijt Rob B. , Asperen Christi J. van , 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 Valérie , Lasset Christine , Dreyfus Hélène , Leroux Dominique , Hardouin Agnès , Berthet Pascaline , Faivre Laurence , Loustalot Catherine , Noguchi Tetsuro , Sobol Hagay , Rouleau Etienne , Nogues Catherine , Frénay Marc , Vénat-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. , Jønson 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 , Schönbuchner Ines , Caldes Trinidad , de la Hoya Miguel , Aittomäki Kristiina , Nevanlinna Heli , Simard Jacques , Spurdle Amanda B. , Holland Helene , Chen Xiaoqing , Platte Radka , Chenevix-Trench Georgia , Easton Douglas F. 
Published: December 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.