Data from 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: 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: March 2024

<div>Abstract<p>The known breast cancer susceptibility polymorphisms in <i>FGFR2</i>, <i>TNRC9/TOX3</i>, <i>MAP3K1</i>, <i>LSP1</i>, and 2q35 confer increased risks of breast cancer for <i>BRCA1</i> or <i>BRCA2</i> mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in <i>SLC4A7/NEK10</i>, rs6504950 in <i>STXBP4/COX11</i>, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 <i>BRCA1</i> and 7,409 <i>BRCA2</i> 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 <i>BRCA2</i> carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, <i>P</i> = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, <i>P</i> = 0.03, respectively). Neither SNP was associated with breast cancer risk for <i>BRCA1</i> carriers, and rs6504950 was not associated with breast cancer for either <i>BRCA1</i> or <i>BRCA2</i> carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for <i>BRCA2</i> carriers (<i>FGFR2, TOX3, MAP3K1, LSP1</i>, 2q35<i>, SLC4A7</i>, 5p12, <i>P</i> = 7 × 10<sup>−11</sup> − 0.03), but only <i>TOX3</i> and 2q35 were associated with the risk for <i>BRCA1</i> carriers (<i>P</i> = 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 <i>BRCA2</i> mutation carriers, the 5% of <i>BRCA2</i> 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. <i>Cancer Res; 70(23); 9742–54. ©2010 AACR</i>.</p></div>