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Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci.

Publication ,  Journal Article
DeVries, AA; Dennis, J; Tyrer, JP; Peng, P-C; Coetzee, SG; Reyes, AL; Plummer, JT; Davis, BD; Chen, SS; Dezem, FS; Aben, KKH; Anton-Culver, H ...
Published in: J Natl Cancer Inst
November 14, 2022

BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

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Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

November 14, 2022

Volume

114

Issue

11

Start / End Page

1533 / 1544

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Female
  • DNA Copy Number Variations
  • Carcinoma, Ovarian Epithelial
  • Alleles
 

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DeVries, A. A., Dennis, J., Tyrer, J. P., Peng, P.-C., Coetzee, S. G., Reyes, A. L., … Jones, M. R. (2022). Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci. J Natl Cancer Inst, 114(11), 1533–1544. https://doi.org/10.1093/jnci/djac160
DeVries, Amber A., Joe Dennis, Jonathan P. Tyrer, Pei-Chen Peng, Simon G. Coetzee, Alberto L. Reyes, Jasmine T. Plummer, et al. “Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci.J Natl Cancer Inst 114, no. 11 (November 14, 2022): 1533–44. https://doi.org/10.1093/jnci/djac160.
DeVries AA, Dennis J, Tyrer JP, Peng P-C, Coetzee SG, Reyes AL, et al. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci. J Natl Cancer Inst. 2022 Nov 14;114(11):1533–44.
DeVries, Amber A., et al. “Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci.J Natl Cancer Inst, vol. 114, no. 11, Nov. 2022, pp. 1533–44. Pubmed, doi:10.1093/jnci/djac160.
DeVries AA, Dennis J, Tyrer JP, Peng P-C, Coetzee SG, Reyes AL, Plummer JT, Davis BD, Chen SS, Dezem FS, Aben KKH, Anton-Culver H, Antonenkova NN, Beckmann MW, Beeghly-Fadiel A, Berchuck A, Bogdanova NV, Bogdanova-Markov N, Brenton JD, Butzow R, Campbell I, Chang-Claude J, Chenevix-Trench G, Cook LS, DeFazio A, Doherty JA, Dörk T, Eccles DM, Eliassen AH, Fasching PA, Fortner RT, Giles GG, Goode EL, Goodman MT, Gronwald J, OPAL Study Group, AOCS Group, Håkansson N, Hildebrandt MAT, Huff C, Huntsman DG, Jensen A, Kar S, Karlan BY, Khusnutdinova EK, Kiemeney LA, Kjaer SK, Kupryjanczyk J, Labrie M, Lambrechts D, Le ND, Lubiński J, May T, Menon U, Milne RL, Modugno F, Monteiro AN, Moysich KB, Odunsi K, Olsson H, Pearce CL, Pejovic T, Ramus SJ, Riboli E, Riggan MJ, Romieu I, Sandler DP, Schildkraut JM, Setiawan VW, Sieh W, Song H, Sutphen R, Terry KL, Thompson PJ, Titus L, Tworoger SS, Van Nieuwenhuysen E, Edwards DV, Webb PM, Wentzensen N, Whittemore AS, Wolk A, Wu AH, Ziogas A, Freedman ML, Lawrenson K, Pharoah PDP, Easton DF, Gayther SA, Jones MR. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci. J Natl Cancer Inst. 2022 Nov 14;114(11):1533–1544.
Journal cover image

Published In

J Natl Cancer Inst

DOI

EISSN

1460-2105

Publication Date

November 14, 2022

Volume

114

Issue

11

Start / End Page

1533 / 1544

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Female
  • DNA Copy Number Variations
  • Carcinoma, Ovarian Epithelial
  • Alleles