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. 2011 Aug 15;20(16):3304-21.
doi: 10.1093/hmg/ddr226. Epub 2011 May 18.

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Antonis C Antoniou  1 , Christiana Kartsonaki, Olga M Sinilnikova, Penny Soucy, Lesley McGuffog, Sue Healey, Andrew Lee, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Monica Barile, Valeria Pensotti, Barbara Pasini, Riccardo Dolcetti, Giuseppe Giannini, Anna Laura Putignano, Liliana Varesco, Paolo Radice, Phuong L Mai, Mark H Greene, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Uffe Birk Jensen, Dorthe G Crüger, Maria A Caligo, Yael Laitman, Roni Milgrom, Bella Kaufman, Shani Paluch-Shimon, Eitan Friedman, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Hans Ehrencrona, Beatrice Melin; SWE-BRCA; Katherine L Nathanson, Susan M Domchek, Timothy Rebbeck, Ania Jakubowska, Jan Lubinski, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Gorski, Ana Osorio, Teresa Ramón y Cajal, Florentia Fostira, Raquel Andrés, Javier Benitez, Ute Hamann, Frans B Hogervorst, Matti A Rookus, Maartje J Hooning, Marcel R Nelen, Rob B van der Luijt, Theo A M van Os, Christi J van Asperen, Peter Devilee, Hanne E J Meijers-Heijboer, Encarna B Gómez Garcia; HEBON; Susan Peock, Margaret Cook, Debra Frost, Radka Platte, Jean Leyland, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Diana Eccles, Kai-ren Ong, Jackie Cook, Fiona Douglas, Joan Paterson, M John Kennedy, Zosia Miedzybrodzka; EMBRACE; Andrew Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Muriel Belotti, Carole Tirapo, Sylvie Mazoyer, Laure Barjhoux, Christine Lasset, Dominique Leroux, Laurence Faivre, Myriam Bronner, Fabienne Prieur, Catherine Nogues, Etienne Rouleau, Pascal Pujol, Isabelle Coupier, Marc Frénay; CEMO Study Collaborators; John L Hopper, Mary B Daly, Mary B Terry, Esther M John, Saundra S Buys, Yosuf Yassin, Alexander Miron, David Goldgar; Breast Cancer Family Registry; Christian F Singer, Muy-Kheng Tea, Georg Pfeiler, Anne Catharina Dressler, Thomas v O Hansen, Lars Jønson, Bent Ejlertsen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Kenneth Offit, Marion Piedmonte, Gustavo Rodriguez, Laurie Small, John Boggess, Stephanie Blank, Jack Basil, Masoud Azodi, Amanda Ewart Toland, Marco Montagna, Silvia Tognazzo, Simona Agata, Evgeny Imyanitov, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Paul D P Pharoah, Lara Sucheston, Beth Y Karlan, Christine S Walsh, Edith Olah, Aniko Bozsik, Soo-Hwang Teo, Joyce L Seldon, Mary S Beattie, Elizabeth J van Rensburg, Michelle D Sluiter, Orland Diez, Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Ina Ruehl, Raymonda Varon-Mateeva, Karin Kast, Helmut Deissler, Dieter Niederacher, Norbert Arnold, Dorothea Gadzicki, Ines Schönbuchner, Trinidad Caldes, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Martine Dumont, Jocelyne Chiquette, Marc Tischkowitz, Xiaoqing Chen, Jonathan Beesley, Amanda B Spurdle; kConFab investigators; Susan L Neuhausen, Yuan Chun Ding, Zachary Fredericksen, Xianshu Wang, Vernon S Pankratz, Fergus Couch, Jacques Simard, Douglas F Easton, Georgia Chenevix-Trench; CIMBA
Collaborators, Affiliations

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Antonis C Antoniou et al. Hum Mol Genet. .

Abstract

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

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Figures

Figure 1.
Figure 1.
Study-specific per-allele HR estimates for BRCA1 and BRCA2 mutation carriers for SNP rs2046210 at 6q25.1 near ESR1. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% CIs.
Figure 2.
Figure 2.
Country-specific per-allele HR estimates for BRCA1 and BRCA2 mutation carriers for SNP rs9397435 at 6q25.1. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% CIs. Due to the low minor allele frequency at this SNP and small study sample we were unable to obtain study-specific estimates for all studies. Studies were therefore grouped by country of origin.
Figure 3.
Figure 3.
Study-specific per-allele HR estimates for BRCA1 and BRCA2 mutation carriers for SNP rs11249433 at 1p11.2. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% CIs.
See this image and copyright information in PMC

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