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

Anna M. Mulligan, Fergus J. Couch, Daniel Barrowdale, Susan M. Domchek, Diana Eccles, Heli Nevanlinna, Susan J. Ramus, Mark Robson, Mark Sherman, Amanda B. Spurdle, Barbara Wappenschmidt, Andrew Lee, Lesley McGuffog, Sue Healey, Olga M. Sinilnikova, Ramunas Janavicius, Thomas V. Hansen, Finn C. Nielsen, Bent Ejlertsen, Ana OsorioIván 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.J. Meijers-Heijboer, Juul Wijnen, Encarna B. Gómez García, Marcel R. Nelen, C. Marleen Kets, Caroline Seynaeve, Madeleine M.A. Tilanus-Linthorst, Rob B. van der Luijt, Theo V. Os, Matti Rookus, Debra Frost, J. Louise Jones, D. Gareth 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 E. Side, Emma McCann, Alex Murray, Susan Peock, Andrew K. Godwin, Rita K. 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 B. Barkardottir, Penny Soucy, Martine Dumont, Jacques Simard, Marco Montagna, Silvia Tognazzo, Emma D'Andrea, Stephen Fox, Max Yan, Tim Rebbeck, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Henry T. Lynch, Patricia A. Ganz, Gail E. Tomlinson, Xianshu Wang, Zachary Fredericksen, Vernon S. Pankratz, Noralane M. Lindor, Csilla Szabo, Kenneth Offit, Rita Sakr, Mia Gaudet, Jasmine Bhatia, Noah Kauff, Christian F. Singer, Muy Kheng Tea, Daphne gschwantler-kaulich, Anneliese Fink-Retter, Phuong L. Mai, Mark H. Greene, Evgeny Imyanitov, Frances P. O'Malley, Hilmi Ozcelik, Gordon Glendon, Amanda E. Toland, Anne Marie Gerdes, Mads Thomassen, Torben A. Kruse, Uffe B. Jensen, Anne Bine Skytte, Maria A. Caligo, Maria Soller, Karin Henriksson, von Anna Wachenfeldt, Brita Arver, Marie Stenmark-Askmalm, Per Karlsson, Yuan C. Ding, Susan L. Neuhausen, Mary Beattie, Paul D.P. Pharoah, Kirsten B. Moysich, Katherine L. Nathanson, Beth Y. Karlan, Jenny Gross, Esther M. John, Mary B. Daly, Saundra M. Buys, Melissa C. Southey, John L. Hopper, Mary B. Terry, Wendy Chung, Alexander F. Miron, David Goldgar, Georgia Chenevix-Trench, Douglas F. Easton, Irene L. Andrulis, Antonis C. Antoniou

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Abstract

Introduction: 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.

Original languageEnglish (US)
Article numberR110
JournalBreast Cancer Research
Volume13
Issue number6
DOIs
StatePublished - Nov 2 2011

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Mulligan, A. M., Couch, F. J., Barrowdale, D., Domchek, S. M., Eccles, D., Nevanlinna, H., Ramus, S. J., Robson, M., Sherman, M., Spurdle, A. B., Wappenschmidt, B., Lee, A., McGuffog, L., Healey, S., Sinilnikova, O. M., Janavicius, R., Hansen, T. V., Nielsen, F. C., Ejlertsen, B., ... Antoniou, A. C. (2011). 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. Breast Cancer Research, 13(6), [R110]. https://doi.org/10.1186/bcr3052