Title Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA 1 and BRCA 2 mutation carriers

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 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. Introduction Women who carry pathogenic mutations in BRCA1 or BRCA2 have markedly increased risks of developing breast cancer. The distributions of breast cancer tumor characteristics differ between BRCA1 mutation carriers, BRCA2 mutation carriers and those arising in the general population. The majority of breast tumors arising in BRCA1 carriers show low or absent expression of estrogen receptor (ER) [1-3], whereas the majority of BRCA2associated tumors are ER-positive [1,4,5]. Many common breast cancer susceptibility alleles identified through population-based genome-wide association studies (GWASs) have also been associated with breast cancer risk in BRCA1 and BRCA2 carriers [6,7]. Several of these variants are specifically associated with the ER status of the breast cancer in the general population [8,9]. Among the single-nucleotide polymorphisms (SNPs) that have been evaluated in mutation carriers so far, the variants found to be associated with breast cancer risk for BRCA1 carriers largely overlap with loci for which stronger associations with ER-negative breast cancer have been reported in the general population [8-12]. An important question for risk modelling and prevention studies is whether the effects of common variants on breast cancer risk in mutation carriers are mediated through a generic influence on the development of particular hormone receptor subtypes of breast cancer or through epistatic interaction with the BRCA1/2 mutation itself. Previous studies by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) described the impact of 29 breast cancer susceptibility variants from nonhereditary breast cancer studies on ER-positive and ERnegative breast cancer risk in BRCA1 and BRCA2 carriers [6,7,13-15]. These analyses demonstrated that, despite the lack of an association between some susceptibility variants and overall breast cancer risk for BRCA1 Kuchenbaecker et al. Breast Cancer Research (2014) 16:3416 Page 3 of 27 or BRCA2 carriers, residual associations exist with specific disease subtypes. In addition, the ER-specific associations in BRCA1 and BRCA2 carriers were mainly in the same direction and of a magnitude similar to the associations observed with breast cancer stratified by ER expression status in the general population. However, these studies were conducted on smaller numbers of mutation carriers than currently available and evaluated only a subset of the currently known breast cancer susceptibility alleles for their associations with ER-specific subtypes in carriers. Recently, 45 additional SNPs have been found to be associated with breast cancer risk in the general population [8-10,16]. Eighteen of these SNPs showed evidence of association with ER-positive breast cancer, but not with ER-negative breast cancer, and four loci (1q32.1 LGR6, 2p24.1, 16q12 and 20q11) were associated only with ER-negative breast cancer in the general population. These 45 newly discovered loci have not yet been evaluated for their associations with breast cancer risk for mutation carriers. In the present study, we assessed the disease subtypespecific associations of all 74 previously reported breast cancer susceptibility variants in 15,252 BRCA1 and 8,211 BRCA2 carriers. We evaluated whether differences in associations of known breast cancer susceptibility variants between BRCA1 carriers, BRCA2 carriers and the general population are mediated by tumor ER status in mutation carriers. We also analyzed the associations of about 200,000 variants on the iCOGS genotyping array with subtype-specific breast cancer risk in carriers in an attempt to uncover previously unreported subtypespecific associations in women with BRCA1 and BRCA2 mutations. In addition to ER and progesterone receptor (PR) status, we report, for the first time to our knowledge, associations by HER2 status and with triplenegative disease (TN, referring to ER-, PRand human epidermal growth factor receptor 2 (HER2)-negative), and we also describe associations with clinical features such as “ductal, no specified subtype” (hereafter referred to as ductal) and lobular morphologic subtypes, nodal status and histological grade.