Abstract
Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g., ESR1, FGFR2, and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10-8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10-9) and one new noncoding variant at 7q21.11 (P < 5 × 10-8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 × 10-8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 × 10-8) and CNFN (P = 3.77 × 10-4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.Significance: Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. Cancer Res; 78(11); 3087-97. ©2018 AACR.
Highlights
Breast cancer is the most common type of cancer and the leading cause of cancer-related deaths in women worldwide [1]
125 breast cancer susceptibility single-nucleotide polymorphisms (SNP) within 98 loci have been discovered at genome-wide significance (P < 5 Â 10À8) (Supplementary Table S1)
Protein–protein interaction and pathway enrichment analysis we evaluated the connectivity at the protein–protein interaction (PPI) level for the genes at 98 previously reported genome-wide association studies (GWAS) loci in breast cancer (Supplementary Table S4) and the three novel loci discovered in this study (Table 2)
Summary
Breast cancer is the most common type of cancer and the leading cause of cancer-related deaths in women worldwide [1]. Dated, increasing evidence indicated that common genetic variants may contribute to the heritable risk of breast cancer [3]. Our understanding of the genetic architecture of breast cancer has been rapidly increased through genome-wide association studies (GWAS), which have identified numerous breast cancer risk– associated variants within more than 90 susceptibility loci (www.genome.gov/gwastudies). These variants only explain a small proportion of the genetic variation in breast cancer. Most of the previously identified variants related to breast cancer susceptibility are located in noncoding genomic regions [6] and provide few clues to the functional mechanisms through which these variants affect susceptibility to the disease. To assess the role of coding variants with high penetrance that were poorly covered in conventional GWAS may contribute to identifying the "missing heritability" in polygenic disorders [7,8,9]
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