Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Abstract

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Improvement in risk prediction, early detection and prevention of breast cancer in the NHS Breast Screening Programme and family history clinics: a dual cohort study

“…This difference in risk could be partly explained by low-risk genetic variants, such as the SNPs identified in GWAS. The current analysis validates the work of CIMBA and suggests that use of SNPs with the BRCA2-related weightings 137 or the Turnbull weightings 131 can be used to advise women within a range of breast cancer lifetime risks of between 42% and 96%. Clinicians could use the SNP multiplicative risk alongside family history of breast cancer and other risk factors to give a better indication of where their risk is likely to lie in this range.…”

“…Cumulative hazard curves were calculated using the Nelson-Aalen estimator 136 and the Cox proportional hazards 137 model was used to assess the relationship between breast cancer risk and overall breast cancer risk score (which was split into quintiles and entered into the model as an ordinal categorical variable) and calculate the HRs. The proportional hazards assumption was assessed graphically by plotting -ln(-ln(survival)) versus ln(time) for each of the five risk groups and checking to see that the curves are parallel.…”

“…To obtain an overall breast cancer risk score for each woman, we multiplied the ORs for each of her 18 genotypes together. As a subset of three SNPs (TOX3, 2q and 6q25.1) has now been validated to be associated with increased risk of breast cancer in BRCA1 mutation carriers, 136 and another subset of nine SNPs (FGFR2, TOX3, MAP3K, 2q, 1p11.2, SLC4A7, 6q25.1, LSP1 and 5p12) in BRCA2 mutation carriers, 136,137 we repeated the analysis using only these SNPs. Finally, we calculated an alternative overall breast cancer risk score based on a combination of SNPs validated to increase risk in BRCA1/BRCA2 mutation carriers and SNPs not yet validated in BRCA1/BRCA2 mutation carriers, that is, all of the original 18 breast cancer susceptibility SNPs, except for those that have been shown to have no association with breast cancer risk in BRCA1/BRCA2 mutation carriers.…”

“…As a result, the cumulative risks to 70 years would be predicted to be substantially lower in an unaffected woman tested aged 20 years. In reality, the predicted risks can be used from the range provided by Antoniou et al, 136,137 and even this may widen as more validated SNPs are added. The performance of the Cox model to predict the order in which a pair of women would develop breast cancer was disappointing but not surprising, given the overlap between the risk groups as regards age at diagnosis.…”

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X

“…22,23 Some of these common alleles have been reported to modify risk in BRCA1 and BRCA2 mutations carriers. 24 However, so far the results from genome-wide association studies have limited value for individual risk prediction, 25 as compared with the high-penetrance inherited mutations in causal genes for familial breast cancer which can prompt drastic clinical intervention such as mastectomy. An analysis to evaluate the potential for individualized disease risk stratification based on common single-nucleotide polymorphisms identified by genome-wide association studies in breast cancer came to the conclusion that the clinical utility of single, common, low-penetrance genes for breast cancer risk prediction is currently quite limited.…”