Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk

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.

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.

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 = 2.57; P = 0.001) and a deletion at CYP2A7 (OR = 1.90; P = 0.007) that were strongly associated with HGSOC risk (OR = 3.02; P = 8.98 × 10^-5). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P = 2.94 × 10^-47). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR = 0.33; P = 9.5 × 10^-2), and somatic deletions correlated with ERBB4 downregulation (P = 7.05 × 10^-5). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR = 0.28; P = 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P = 2.7 × 10^-7), and another at 8p21.2 (OR = 0.52; P = 0.002) that was present somatically where it correlated with lower GNRH1 expression (P = 5.9 × 10^-5).

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.

Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.