Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Abstract

IntroductionPrevious studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.MethodsWe used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.ResultsThe results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.ConclusionsThe associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2mutation carriers

“…The analysis was carried out by an extension of the retrospective likelihood approach to model the simultaneous effect of each SNP on more than one tumour subtype [14]. Briefly, this involves modelling the conditional likelihood of the observed SNP genotypes and tumour subtypes, given the disease phenotypes.…”

Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

“…Class 1 mutations are predicted to undergo nonsense mediated RNA decay resulting in reduced levels of mutant transcript while Class 2 mutations are predicted to generate stable mutant proteins (11). The associations with breast cancer subtypes defined by the estrogen receptor (ER) status of the tumors in BRCA1 and BRCA2 mutation carriers were assessed by an extension of the retrospective likelihood approach that models the simultaneous effect of each SNP on more than one tumor subtype (12). Associations with ovarian cancer risk were evaluated within a competing risk analysis framework (13) by estimating HRs simultaneously for breast and ovarian cancers.…”

Cation‐Coupled Bicarbonate Transporters

“…The SNP rs4973768 is tightly linked to increased breast cancer risk for BRCA2 carriers (18,223) and is particularly associated with the Luminal A subtype (127). This SNP is located in the 3′ untranslated region of the SLC4A7 gene, implying that the observed association with breast cancer phenotypes does not involve altered function of the transporter, but instead could be due to a change in NBCn1 mRNA stability.…”