DeVries, Amber A;
Dennis, Joe;
Tyrer, Jonathan P;
Peng, Pei-Chen;
Coetzee, Simon G;
Reyes, Alberto L;
Plummer, Jasmine T;
... Jones, Michelle R; + view all
(2022)
Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci.
JNCI: Journal of the National Cancer Institute
10.1093/jnci/djac160.
(In press).
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/jnci/djac160 |
| Publisher version: | https://doi.org/10.1093/jnci/djac160 |
| Language: | English |
| Additional information: | © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10157404 |
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