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.
Highlights
Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
The FGFR2 single nucleotide polymorphisms (SNPs) rs2981582 exhibited the clearest difference with a strong association for ER-positive disease but not ER-negative disease
There was no significant evidence of differences between the hazard ratio (HR) for ER-positive and ER-negative breast cancer, the TOX3/TNRC9 SNP rs3803662 was significantly associated with the risk of ER-positive disease but not with risk for ER-negative breast cancer
Summary
Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast cancer risks for mutation carriers were found to vary according to the age at diagnosis and the type of cancer of the index patient involved in the family ascertainment [6,7,11]. Such evidence suggests that genetic or other risk factors that cluster in families modify the cancer risks conferred by BRCA1 and BRCA2 mutations. Adjusting for grade, BRCA2-associated tumours are more often ER-positive and are less likely, compared with controls, to express the basal cytokeratin CK5 or to overexpress HER2/neu protein [17]
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