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

Journal: Breast Cancer Research : BCR

Published: January 01, 2014

Abstract

Background: 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.

Authors

Karoline Kuchenbaecker, Susan Neuhausen, Mark Robson, Daniel Barrowdale, Lesley Mcguffog, Anna Mulligan, Irene Andrulis, Amanda Spurdle, Marjanka Schmidt, Rita Schmutzler, Christoph Engel, Barbara Wappenschmidt, Heli Nevanlinna, Mads Thomassen, Melissa Southey, Paolo Radice, Susan Ramus, Susan Domchek, Katherine Nathanson, Andrew Lee, Sue Healey, Robert Nussbaum, Timothy Rebbeck, Banu Arun, Paul James, Beth Karlan, Jenny Lester, Ilana Cass, Mary Daly, David Goldgar, Saundra Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia Dorfling, Elizabeth Van Rensburg, Linda Steele, Thomas V O Hansen, Bent Ejlertsen, Anne-marie Gerdes, Finn Nielsen, Joe Dennis, Julie Cunningham, Steven Hart, Susan Slager, Ana Osorio, Javier Benitez, Mercedes Duran, Jeffrey 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 Tibiletti, Giuseppe Giannini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Carole Brewer, Claire Foo, D Evans, Debra Frost, Diana Eccles, Fiona Douglas, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Kai-ren Ong, Lisa Walker, Louise Izatt, Lucy Side, M Kennedy, Mark Rogers, Mary Porteous, Patrick Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Andrew 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, Laure Barjhoux, Laurence Faivre, Nicolas Sevenet, Olga Sinilnikova, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux Moncoutier, Claudine Isaacs, Tom Van Maerken, Kathleen Claes, Marion Piedmonte, Lesley Andrews, John Hays, Gustavo Rodriguez, Trinidad Caldes, Miguel De La Hoya, Sofia Khan, Frans B Hogervorst, Cora Aalfs, J De Lange, Hanne E Meijers Heijboer, Annemarie Van Der Hout, Juul Wijnen, K E Van Roozendaal, Arjen Mensenkamp, Ans M Van Den Ouweland, Carolien H Van Deurzen, Rob Van Der Luijt, Edith Olah, Orland Diez, Conxi Lazaro, 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 Teixeira, Curtis Olswold, Noralane Lindor, Vernon Pankratz, Emily Hallberg, Csilla Szabo, Joseph Vijai, Lauren Jacobs, Marina Corines, Anne Lincoln, Andreas Berger, Anneliese Fink Retter, Christian Singer, Christine Rappaport, Daphne Kaulich, Georg Pfeiler, Muy-kheng Tea, Catherine Phelan, Phuong Mai, Mark Greene, Gad Rennert, Evgeny Imyanitov, Gord Glendon, Amanda Toland, Anders Bojesen, Inge Pedersen, Uffe Jensen, Maria Caligo, Eitan Friedman, Raanan Berger, Yael Laitman, Johanna Rantala, Brita Arver, Niklas Loman, Ake Borg, Hans Ehrencrona, Olufunmilayo Olopade, Jacques Simard, Douglas Easton, Georgia Chenevix Trench, Kenneth Offit, Fergus Couch, Antonis Antoniou

Relevant Conditions

Breast Cancer

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

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