Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

Journal: Breast Cancer Research : BCR

Published: April 27, 2011

Abstract

Background: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.

Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.

Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.

Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Authors

Anna Mulligan, Fergus Couch, Daniel Barrowdale, Susan Domchek, Diana Eccles, Heli Nevanlinna, Susan Ramus, Mark Robson, Mark Sherman, Amanda Spurdle, Barbara Wappenschmidt, Andrew Lee, Lesley Mcguffog, Sue Healey, Olga Sinilnikova, Ramunas Janavicius, Thomas Hansen, Finn Nielsen, Bent Ejlertsen, Ana Osorio, Iván Muñoz Repeto, Mercedes Durán, Javier Godino, Maroulio Pertesi, Javier Benítez, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Bernardo Bonanni, Alessandra Viel, Barbara Pasini, Laura Papi, Laura Ottini, Antonella Savarese, Loris Bernard, Paolo Radice, Ute Hamann, Martijn Verheus, Hanne E Meijers Heijboer, Juul Wijnen, Encarna Gómez García, Marcel Nelen, C Kets, Caroline Seynaeve, Madeleine M Tilanus Linthorst, Rob Van Der Luijt, Theo Van Os, Matti Rookus, Debra Frost, J Jones, D Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Jackie Cook, Alan Donaldson, Huw Dorkins, Helen Gregory, Jacqueline Eason, Catherine Houghton, Julian Barwell, Lucy Side, Emma Mccann, Alex Murray, Susan Peock, Andrew Godwin, Rita Schmutzler, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Ina Ruehl, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Karin Kast, Sabine Preisler Adams, Raymonda Varon Mateeva, Ines Schoenbuchner, Britta Fiebig, Wolfram Heinritz, Dieter Schäfer, Heidrun Gevensleben, Virginie Caux Moncoutier, Marion Fassy Colcombet, François Cornelis, Sylvie Mazoyer, Mélanie Léoné, Nadia Boutry Kryza, Agnès Hardouin, Pascaline Berthet, Danièle Muller, Jean-pierre Fricker, Isabelle Mortemousque, Pascal Pujol, Isabelle Coupier, Marine Lebrun, Caroline Kientz, Michel Longy, Nicolas Sevenet, Dominique Stoppa Lyonnet, Claudine Isaacs, Trinidad Caldes, Miguel De La Hoya, Tuomas Heikkinen, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Rosa Barkardottir, Penny Soucy, Martine Dumont, Jacques Simard, Marco Montagna, Silvia Tognazzo, Emma D'andrea, Stephen Fox, Max Yan, Tim Rebbeck, Olufunmilayo Olopade, Jeffrey Weitzel, Henry Lynch, Patricia Ganz, Gail Tomlinson, Xianshu Wang, Zachary Fredericksen, Vernon Pankratz, Noralane Lindor, Csilla Szabo, Kenneth Offit, Rita Sakr, Mia Gaudet, Jasmine Bhatia, Noah Kauff, Christian Singer, Muy-kheng Tea, Daphne Gschwantler Kaulich, Anneliese Fink Retter, Phuong Mai, Mark Greene, Evgeny Imyanitov, Frances O'malley, Hilmi Ozcelik, Gordon Glendon, Amanda Toland, Anne-marie Gerdes, Mads Thomassen, Torben Kruse, Uffe Jensen, Anne-bine Skytte, Maria Caligo, Maria Soller, Karin Henriksson, Von Wachenfeldt, Brita Arver, Marie Stenmark Askmalm, Per Karlsson, Yuan Ding, Susan Neuhausen, Mary Beattie, Paul D Pharoah, Kirsten Moysich, Katherine Nathanson, Beth Karlan, Jenny Gross, Esther John, Mary Daly, Saundra Buys, Melissa Southey, John Hopper, Mary Terry, Wendy Chung, Alexander Miron, David Goldgar, Georgia Chenevix Trench, Douglas Easton, Irene Andrulis, Antonis Antoniou

Relevant Conditions

Breast Cancer

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

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