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

Journal Article (Journal Article)

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 = 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). 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.

Full Text

Duke Authors

Cited Authors

  • Reid, BM; Permuth, JB; Chen, YA; Fridley, BL; Iversen, ES; Chen, Z; Jim, H; Vierkant, RA; Cunningham, JM; Barnholtz-Sloan, JS; Narod, S; Risch, H; Schildkraut, JM; Goode, EL; Monteiro, AN; Sellers, TA

Published Date

  • July 2019

Published In

Volume / Issue

  • 28 / 7

Start / End Page

  • 1117 - 1126

PubMed ID

  • 30948450

Pubmed Central ID

  • 30948450

Electronic International Standard Serial Number (EISSN)

  • 1538-7755

Digital Object Identifier (DOI)

  • 10.1158/1055-9965.EPI-18-0833


  • eng

Conference Location

  • United States