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

Publication ,  Journal Article
Reid, BM; Permuth, JB; Chen, YA; Fridley, BL; Iversen, ES; Chen, Z; Jim, H; Vierkant, RA; Cunningham, JM; Barnholtz-Sloan, JS; Narod, S ...
Published in: Cancer Epidemiol Biomarkers Prev
July 2019

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.

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Published In

Cancer Epidemiol Biomarkers Prev

DOI

EISSN

1538-7755

Publication Date

July 2019

Volume

28

Issue

7

Start / End Page

1117 / 1126

Location

United States

Related Subject Headings

  • Humans
  • Genome-Wide Association Study
  • Female
  • Epidemiology
  • DNA Copy Number Variations
  • Case-Control Studies
  • Carcinoma, Ovarian Epithelial
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 11 Medical and Health Sciences
 

Citation

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Reid, B. M., Permuth, J. B., Chen, Y. A., Fridley, B. L., Iversen, E. S., Chen, Z., … Sellers, T. A. (2019). Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk. Cancer Epidemiol Biomarkers Prev, 28(7), 1117–1126. https://doi.org/10.1158/1055-9965.EPI-18-0833
Reid, Brett M., Jennifer B. Permuth, Y Ann Chen, Brooke L. Fridley, Edwin S. Iversen, Zhihua Chen, Heather Jim, et al. “Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk.Cancer Epidemiol Biomarkers Prev 28, no. 7 (July 2019): 1117–26. https://doi.org/10.1158/1055-9965.EPI-18-0833.
Reid BM, Permuth JB, Chen YA, Fridley BL, Iversen ES, Chen Z, et al. Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2019 Jul;28(7):1117–26.
Reid, Brett M., et al. “Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk.Cancer Epidemiol Biomarkers Prev, vol. 28, no. 7, July 2019, pp. 1117–26. Pubmed, doi:10.1158/1055-9965.EPI-18-0833.
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. Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2019 Jul;28(7):1117–1126.

Published In

Cancer Epidemiol Biomarkers Prev

DOI

EISSN

1538-7755

Publication Date

July 2019

Volume

28

Issue

7

Start / End Page

1117 / 1126

Location

United States

Related Subject Headings

  • Humans
  • Genome-Wide Association Study
  • Female
  • Epidemiology
  • DNA Copy Number Variations
  • Case-Control Studies
  • Carcinoma, Ovarian Epithelial
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 11 Medical and Health Sciences