Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
Authors: Kuchenbaecker Karoline B , Neuhausen Susan L , Robson Mark , Barrowdale Daniel , McGuffog Lesley , Mulligan Anna Marie , Andrulis Irene L , Spurdle Amanda B , Schmidt Marjanka K , Schmutzler Rita K , Engel Christoph , Wappenschmidt Barbara , Nevanlinna Heli , Thomassen Mads , Southey Melissa , Radice Paolo , Ramus Susan J , Domchek Susan M , Nathanson Katherine L , Lee Andrew , Healey Sue , Nussbaum Robert L , Rebbeck Timothy R , Arun Banu K , James Paul , Karlan Beth Y , Lester Jenny , Cass Ilana , Registry Breast Cancer Family , Terry Mary Beth , Daly Mary B , Goldgar David E , Buys Saundra S , Janavicius Ramunas , Tihomirova Laima , Tung Nadine , Dorfling Cecilia M , van Rensburg Elizabeth J , Steele Linda , v O Hansen Thomas , Ejlertsen Bent , Gerdes Anne-Marie , Nielsen Finn C , Dennis Joe , Cunningham Julie , Hart Steven , Slager Susan , Osorio Ana , Benitez Javier , Duran Mercedes , Weitzel Jeffrey N , Tafur Isaac , Hander Mary , Peterlongo Paolo , Manoukian Siranoush , Peissel Bernard , Roversi Gaia , Scuvera Giulietta , Bonanni Bernardo , Mariani Paolo , Volorio Sara , Dolcetti Riccardo , Varesco Liliana , Papi Laura , Tibiletti Maria Grazia , Giannini Giuseppe , Fostira Florentia , Konstantopoulou Irene , Garber Judy , Hamann Ute , Donaldson Alan , Brewer Carole , Foo Claire , Evans D Gareth , Frost Debra , Eccles Diana , Douglas Fiona , Brady Angela , Cook Jackie , Tischkowitz Marc , Adlard Julian , Barwell Julian , Ong Kai-ren , Walker Lisa , Izatt Louise , Side Lucy E , Kennedy M John , Rogers Mark T , Porteous Mary E , Morrison Patrick J , Platte Radka , Eeles Ros , Davidson Rosemarie , Hodgson Shirley , Ellis Steve , Godwin Andrew K , Rhiem Kerstin , Meindl Alfons , Ditsch Nina , Arnold Norbert , Plendl Hansjoerg , Niederacher Dieter , Sutter Christian , Steinemann Doris , Bogdanova-Markov Nadja , Kast Karin , Varon-Mateeva Raymonda , Wang-Gohrke Shan , Gehrig Andrea , Markiefka Birgid , Buecher Bruno , Lefol Cédrick , Stoppa-Lyonnet Dominique , Rouleau Etienne , Prieur Fabienne , Damiola Francesca , Barjhoux Laure , Faivre Laurence , Longy Michel , Sevenet Nicolas , Sinilnikova Olga M , Mazoyer Sylvie , Bonadona Valérie , Caux-Moncoutier Virginie , Isaacs Claudine , Van Maerken Tom , Claes Kathleen , Piedmonte Marion , Andrews Lesley , Hays John , Rodriguez Gustavo C , Caldes Trinidad , de la Hoya Miguel , Khan Sofia , Hogervorst Frans BL , Aalfs Cora M , de Lange JL , Meijers-Heijboer Hanne EJ , van der Hout Annemarie H , Wijnen Juul T , van Roozendaal KEP , Mensenkamp Arjen R , van den Ouweland Ans MW , van Deurzen Carolien HM , van der Luijt Rob B , Olah Edith , Diez Orland , Lazaro Conxi , Blanco Ignacio , Teulé Alex , Menendez Mireia , Jakubowska Anna , Lubinski Jan , Cybulski Cezary , Gronwald Jacek , Jaworska-Bieniek Katarzyna , Durda Katarzyna , Arason Adalgeir , Maugard Christine , Soucy Penny , Montagna Marco , Agata Simona , Teixeira Manuel R , Olswold Curtis , Lindor Noralane , Pankratz Vernon S , Hallberg Emily , Wang Xianshu , Szabo Csilla I , Vijai Joseph , Jacobs Lauren , Corines Marina , Lincoln Anne , Berger Andreas , Fink-Retter Anneliese , Singer Christian F , Rappaport Christine , Kaulich Daphne Gschwantler , Pfeiler Georg , Tea Muy-Kheng , Phelan Catherine M , Mai Phuong L , Greene Mark H , Rennert Gad , Imyanitov Evgeny N , Glendon Gord , Toland Amanda Ewart , Bojesen Anders , Pedersen Inge Sokilde , Jensen Uffe Birk , Caligo Maria A , Friedman Eitan , Berger Raanan , Laitman Yael , Rantala Johanna , Arver Brita , Loman Niklas , Borg Ake , Ehrencrona Hans , Olopade Olufunmilayo I , Simard Jacques , Easton Douglas F , Chenevix-Trench Georgia , Offit Kenneth , Couch Fergus J , Antoniou Antonis C ,   EMBRACE Study,   GEMO Study Collaborators,   HEBON,   KConFab Investigators
Published: December 2014

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.