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

Abstract

IntroductionMore 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.MethodsWe 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.ResultsThe 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.ConclusionsDifferences 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0492-9) contains supplementary material, which is available to authorized users.

Modifiers of breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers

“…A systematic evaluation of the associations of 74 known breast cancer susceptibility alleles found that their associations with ER-positive breast cancer for BRCA1 and BRCA2 mutation carriers were more consistent with the associations of these SNPs with ER-positive breast cancer in the general population. Furthermore, the associations of these SNPs with ER-negative breast cancer for BRCA1 and BRCA2 mutation carriers were more consistent with the associations of the SNPs with ER-negative breast cancer in the general population (Kuchenbaecker et al 2014). Similarly, common variants associated with the risk of serous ovarian cancer in the general population are associated with overall ovarian cancer risk for carriers of mutations in both genes (approximately two-thirds of whom develop serous disease) (Mavaddat et al 2012).…”

“…In this context, within CIMBA, four approaches have been applied to identify loci associated with breast and ovarian cancer for mutation carriers: (i) GWAS for breast and ovarian cancer specifically performed in samples of BRCA1 and BRCA2 mutation carriers (Antoniou et al 2010b, Gaudet et al 2013; (ii) association 23:10 studies to assess common breast and ovarian cancer susceptibility alleles identified in the general population as potential modifiers of risk for mutation carriers (Antoniou et al 2008b, Kuchenbaecker et al 2014; (iii) meta-analyses of GWAS performed in BRCA1 and BRCA2 mutation carriers with GWAS of related phenotypes in the general population (for example, combining studies of breast cancer risk for BRCA1 mutation carriers with those of oestrogen receptor-negative breast cancer in general population or studies of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers with GWAS of serous ovarian cancer in the general population) (Kuchenbaecker et al 2015, Couch et al 2016; and iv) finescale mapping of risk-modifying loci identified through GWAS approaches to fully characterise the associations with all genetic variants at these loci (Bojesen et al 2013, Dunning et al 2016, Lawrenson et al 2016.…”

“…More specifically, susceptibility loci for overall and oestrogen receptor (ER)-positive breast cancer for women in the general population tend to be associated with overall breast cancer risk for BRCA2 mutation carriers (who mostly (70-80%) develop ER-positive disease (Mavaddat et al 2012)), whereas those for ER-negative breast cancer tend to be associated with overall risk for BRCA1 mutation carriers (who mostly (70-80%) develop ER-negative disease (Mavaddat et al 2012)) (Milne & Antoniou 2011, Kuchenbaecker et al 2014. A systematic evaluation of the associations of 74 known breast cancer susceptibility alleles found that their associations with ER-positive breast cancer for BRCA1 and BRCA2 mutation carriers were more consistent with the associations of these SNPs with ER-positive breast cancer in the general population.…”

“…However, analyses based on smaller subsets of SNPs suggest no evidence of departure from the multiplicative model for the joint effects of SNPs (Antoniou et al 2008b(Antoniou et al , 2010a, as observed in the general population. Given the observed differences between BRCA1 and BRCA2 mutation carriers in the association patterns of the common genetic variants with breast cancer risk and their consistency with associations with ER-negative and ER-positive disease, respectively, the most likely underlying model of genetic susceptibility to breast cancer is one where the associated effects of common susceptibility variants and of BRCA1 and BRCA2 mutations on breast cancer risk would be multiplicative, after taking into account tumour ER status (Kuchenbaecker et al 2014). …”

TIM-3 expression in breast cancer

“…These patients were diagnosed with invasive breast cancer at the University of British Columbia hospitals between 1989 and 2002 and have been previously described 44 . A detailed description of the validation set consisting of 3,992 breast cancer patients has been previously published 45,46 . In brief, newly diagnosed invasive breast cancers from centres across the province of British Columbia performing breast cancer excision surgery, referred to the British Columbia Cancer Agency (BCCA) between 1986 and 1992 and for which both blocks from a central estrogen receptor testing laboratory and detailed clinico-pathologic, treatment and outcome data collected by the BCCA Breast Cancer Outcomes Unit were available were assembled into 17 single core tissue microarray blocks.…”