Background: Germline DNA copy number variation (CNV) is a ubiquitous source of genetic variation and remains largely unexplored in association with epithelial ovarian cancer (EOC) risk. Methods: CNV was quantified in the DNA of approximately 3,500 cases and controls genotyped with the Illumina 610k and HumanOmni2.5M arrays. We performed a genome-wide association study of common (>1%) CNV regions (CNVRs) with EOC and high-grade serous (HGSOC) risk and, using The Cancer Genome Atlas (TCGA), performed in silico analyses of tumor-gene expression. Results: Three CNVRs were associated (P < 0.01) with EOC risk: two large (100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR ¼ 2.57; P ¼ 0.001) and a deletion at CYP2A7 (OR ¼ 1.90; P ¼ 0.007) that were strongly associated with HGSOC risk (OR ¼ 3.02; P ¼ 8.98 105). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P ¼ 2.94 1047). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR ¼ 0.33; P ¼ 9.5 102), and somatic deletions correlated with ERBB4 downregulation (P ¼ 7.05 105). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR ¼ 0.28; P ¼ 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P ¼ 2.7 107), and another at 8p21.2 (OR ¼ 0.52; P ¼ 0.002) that was present somatically where it correlated with lower GNRH1 expression (P ¼ 5.9 105). Conclusions: Though CNV appears to not contribute largely to EOC susceptibility, a number of low-to-common frequency variants may influence the risk of EOC and tumor-gene expression. Impact: Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.
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