Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Karoline B. Kuchenbaecker, Susan L. Neuhausen, Mark Robson, Daniel Barrowdale, Lesley McGuffog, Anna Marie Mulligan, Irene L. Andrulis, Amanda B. Spurdle, Marjanka K. Schmidt, Rita K. Schmutzler, Christoph Engel, Barbara Wappenschmidt, Heli Nevanlinna, Mads Thomassen, Melissa Southey, Paolo Radice, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Andrew LeeSue Healey, Robert L. Nussbaum, Timothy R. Rebbeck, Banu K. Arun, Paul James, Beth Y. Karlan, Jenny Lester, Ilana Cass, Mary Beth Terry, Mary B. Daly, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Thomas v O Hansen, Bent Ejlertsen, Anne Marie Gerdes, Finn C. Nielsen, Joe Dennis, Julie Cunningham, Steven Hart, Susan Slager, Ana Osorio, Javier Benitez, Mercedes Duran, Jeffrey N. Weitzel, Isaac Tafur, Mary Hander, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Gaia Roversi, Giulietta Scuvera, Bernardo Bonanni, Paolo Mariani, Sara Volorio, Riccardo Dolcetti, Liliana Varesco, Laura Papi, Maria Grazia Tibiletti, Giuseppe Giannini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Carole Brewer, Claire Foo, D. Gareth Evans, Debra Frost, Diana Eccles, EMBRACE Study, Fiona Douglas, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Kai ren Ong, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Andrew K. Godwin, Kerstin Rhiem, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Doris Steinemann, Nadja Bogdanova-Markov, Karin Kast, Raymonda Varon-Mateeva, Shan Wang-Gohrke, Andrea Gehrig, Birgid Markiefka, Bruno Buecher, Cédrick Lefol, Dominique Stoppa-Lyonnet, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, GEMO Study Collaborators, Laure Barjhoux, Laurence Faivre, Michel Longy, Nicolas Sevenet, Olga M. Sinilnikova, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Claudine Isaacs, Tom Van Maerken, Kathleen Claes, Marion Piedmonte, Lesley Andrews, John Hays, Gustavo C. Rodriguez, Trinidad Caldes, Miguel de la Hoya, Sofia Khan, Frans B.L. Hogervorst, Cora M. Aalfs, J. L. de Lange, Hanne E.J. Meijers-Heijboer, Annemarie H. van der Hout, Juul T. Wijnen, K. E.P. van Roozendaal, Arjen R. Mensenkamp, Ans M.W. van den Ouweland, Carolien H.M. van Deurzen, Rob B. van der Luijt, Edith Olah, Orland Diez, Conxi Lazaro, Ignacio Blanco, Alex Teulé, Mireia Menendez, Anna Jakubowska, Jan Lubinski, Cezary Cybulski, Jacek Gronwald, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Adalgeir Arason, Christine Maugard, Penny Soucy, Marco Montagna, Simona Agata, Manuel R. Teixeira, kConFab Investigators, Curtis Olswold, Noralane Lindor, Vernon S. Pankratz, Emily Hallberg, Xianshu Wang, Csilla I. Szabo, Joseph Vijai, Lauren Jacobs, Marina Corines, Anne Lincoln, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Gschwantler Kaulich, Georg Pfeiler, Muy Kheng Tea, Catherine M. Phelan, Phuong L. Mai, Mark H. Greene, Gad Rennert, Evgeny N. Imyanitov, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Raanan Berger, Yael Laitman, Johanna Rantala, Brita Arver, Niklas Loman, Ake Borg, Hans Ehrencrona, Olufunmilayo I. Olopade, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Kenneth Offit, Fergus J. Couch, on behalf of CIMBA

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Abstract

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10-6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Original languageEnglish
Article number3416
Number of pages27
JournalBreast Cancer Research
Volume16
DOIs
Publication statusPublished - 31 Dec 2014
Externally publishedYes

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