Abstract
DNA damage and replication checkpoints mediated by the ATR-CHEK1 pathway are key to the maintenance of genome stability, and both ATR and CHEK1 have been proposed as potential breast cancer susceptibility genes. Many novel variants recently identified by the large resequencing projects have not yet been thoroughly tested in genome-wide association studies for breast cancer susceptibility. We therefore used a tagging SNP (tagSNP) approach based on recent SNP data available from the 1000 genomes projects, to investigate the roles of ATR and CHEK1 in breast cancer risk and survival. ATR and CHEK1 tagSNPs were genotyped in the Sheffield Breast Cancer Study (SBCS; 1011 cases and 1024 controls) using Illumina GoldenGate assays. Untyped SNPs were imputed using IMPUTE2, and associations between genotype and breast cancer risk and survival were evaluated using logistic and Cox proportional hazard regression models respectively on a per allele basis. Significant associations were further examined in a meta-analysis of published data or confirmed in the Utah Breast Cancer Study (UBCS). The most significant associations for breast cancer risk in SBCS came from rs6805118 in ATR (p=7.6x10-5) and rs2155388 in CHEK1 (p=3.1x10-6), but neither remained significant after meta-analysis with other studies. However, meta-analysis of published data revealed a weak association between the ATR SNP rs1802904 (minor allele frequency is 12%) and breast cancer risk, with a summary odds ratio (confidence interval) of 0.90 (0.83-0.98) [p=0.0185] for the minor allele. Further replication of this SNP in larger studies is warranted since it is located in the target region of 2 microRNAs. No evidence of any survival effects of ATR or CHEK1 SNPs were identified. We conclude that common alleles of ATR and CHEK1 are not implicated in breast cancer risk or survival, but we cannot exclude effects of rare alleles and of common alleles with very small effect sizes.
Highlights
Despite the successes of the genome-wide association studies (GWAS) in identifying breast cancer susceptibility loci, the level of breast cancer risk explained by these susceptibility loci remains modest [1]
For the chromosome 11: 125445035-125596150 region containing the etoposide induced 2.4 (EI24), STT3A, CHEK1 and ACRV1 genes, the most significant association came from the typed rs2155388 single nucleotide polymorphisms (SNPs) at p value of 3.1x10-6 (Figure 2), with an allelic effect of odds ratio (OR) of 1.43 (Table S4 in File S1)
We identified an association between ATR rs6805118 and breast cancer risk in the Sheffield Breast Cancer Study (SBCS) discovery set
Summary
Despite the successes of the genome-wide association studies (GWAS) in identifying breast cancer susceptibility loci, the level of breast cancer risk explained by these susceptibility loci remains modest [1]. Good coverage of genetic markers, usually single nucleotide polymorphisms (SNPs) that sufficiently represent the surrounding variants through linkage disequilibrium (LD), is essential to a successful screening of susceptibility loci. Not all regions have been well captured, and more genetic markers may be needed. Novel disease susceptibility loci have been identified from the meta-analysis of several GWAS together [2,3], suggesting that some loci are not well captured in the initial GWAS discovery stage, partly due to a lack of power. Many of the resulting novel variants have not yet been thoroughly tested in GWAS
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