Abstract
BackgroundGenome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk.MethodsThe coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located < 500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population. Rare (minor allele frequency ≤ 0.001 in the Exome Aggregation Consortium and Exome Variant Server databases) loss-of-function (LoF) and missense variants were studied.ResultsLoF variants were rare in both the cases and control participants across all the candidate genes, with only 38 different LoF variants observed in a total of 39 carriers. For the majority of genes (n = 36), no LoF variants were detected in either the case or control cohorts. No individual gene showed a significant excess of LoF or missense variants in the cases compared with control participants. Among all candidate genes as a group, the total number of carriers with LoF variants was higher in the cases than in the control participants (26 cases and 13 control participants), as was the total number of carriers with missense variants (406 versus 353), but neither reached statistical significance (p = 0.077 and p = 0.512, respectively). The genes contributing most of the excess of LoF variants in the cases included TET2, NRIP1, RAD51B and SNX32 (12 cases versus 2 control participants), whereas ZNF283 and CASP8 contributed largely to the excess of missense variants (25 cases versus 8 control participants).ConclusionsOur data suggest that rare LoF and missense variants in genes associated with low-penetrance breast cancer risk SNPs may contribute some additional risk, but as a group these genes are unlikely to be major contributors to breast cancer heritability.
Highlights
Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk
Candidate genes Because the target genes influenced by most reported breast cancer predisposition SNPs remain unknown, we used two strategies to identify genes of interest: (1) those reported as the plausible target gene in GWASs at the time of our gene panel design [2, 3, 6,7,8,9,10,11,12,13], and (2) where no gene had previously been proposed for a particular SNP, we screened any gene located ± 500 kb of the risk-associated SNP on the basis that most enhancers are < 500 kb away from the gene that they regulate and that most linkage disequilibrium (LD) blocks are < 500 kb in size [14]
Loss-of-function variants LoF variants were rare in both the cases and control participants across all the candidate genes, with only unique variants observed in a total of carriers (Table 2)
Summary
Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk. We hypothesised that if subtle expression changes confer a low susceptibility to breast cancer, coding variants in some of these genes might confer much higher levels of risk This concept is supported by the finding of low-penetrance SNPs associated with known moderate- and high-penetrance genes such as BRCA2, CHEK2 and potentially RAD51B (RAD51L1) [1,2,3], raising the possibility that other genes associated with lowpenetrance SNPs might be enriched for coding highpenetrance predisposition alleles.
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