A Large-Scale, Exome-Wide Association Study of Han Chinese Women Identifies Three Novel Loci Predisposing to Breast Cancer.

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., <i>ESR1, FGFR2</i>, and <i>TOX3</i>), we identify two novel missense variants in <i>C21orf58</i> (rs13047478, <i>P</i>_meta = 4.52 × 10^-8) and <i>ZNF526</i> (rs3810151, <i>P</i>_meta = 7.60 × 10^-9) and one new noncoding variant at 7q21.11 (<i>P</i> < 5 × 10^-8). <i>C21orf58</i> and <i>ZNF526</i> 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 (<i>P</i> < 5.00 × 10^-8) associated with the expression of genes <i>MCM3AP</i> and <i>YBEY</i> in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes <i>PAFAH1B3</i> (<i>P</i> = 8.39 × 10^-8) and <i>CNFN</i> (<i>P</i> = 3.77 × 10^-4) in human blood samples. <i>C21orf58</i> and <i>ZNF526</i>, 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.<b>Significance:</b> Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. <i>Cancer Res; 78(11); 3087-97. ©2018 AACR</i>.