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

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.

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“…In the context of disease, CNVs have been implicated in a variety of conditions, including developmental disorders, neurodegenerative diseases ( 56 , 57 ). In cancer, CNVs may contribute to tumorigenesis by affecting oncogenes or tumor suppressor genes, disrupting key signaling pathways or altering the genomic stability of cancer cells ( 58 , 59 ).…”

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“…These cell lines do not exhibit the main characteristics of HGSOC, such as high levels of CNV (Copy Number Variation) and the presence mutations in the TP53, BRCA1, and/or BRCA2 genes. Instead, mutations are present in genes other than HGSOC, such as ARID1A (characteristic of endometrioid and clear cell ovarian cancer) and PIK3CA (identified in clear cell ovarian cancer) [26,28]. However, these cell lines are well described in the literature, have long research, and are characterized by high cell viability, low culture requirements, and rapid division.…”

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“…Over the past two decades, many risk factors have been independently associated with the risk of developing breast cancer. Genetic risk factors can explain up to 40% of the inherited breast cancer risk (defined as a doubled familial breast cancer risk) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 . This is contrasted with risk factors that are not associated with genetic risk, which include, for example, reproductive health parameters, weight, or lifestyle factors 27 .…”

“…Viele Risikofaktoren sind in den letzten beiden Jahrzehnten unabhängig voneinander mit dem Brustkrebsrisiko assoziiert worden. Genetische Risikofaktoren können bis zu 40% des vererbbaren Brustkrebsrisikos (definiert als das 2-fach erhöhte familiäre Brustkrebsrisiko) erklären 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 . Demgegenüber stehen Risikofaktoren, die nicht mit einem genetischen Risiko in Zusammenhang gebracht werden können.…”