Genetic Epidemiology


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Family history remains one of the strongest risk factors for ovarian cancer, with a threefold increased risk as compared to a woman with no familial history of disease. Mutations in highly penetrant susceptibility genes are the strongest predictors of inherited risk for ovarian cancer. In the BRCA1 and BRCA2 genes, mutations confer high-penetrance susceptibility to ovarian and breast cancer. In family studies, the cumulative risks of ovarian cancer in BRCA1 and BRCA2 mutation carriers by age 80 years are estimated to be 44% and 17% in respectively.


In a combined analysis of 22 different studies, average risks were 39% in BRCA1-mutation carriers and 11% in BRCA2-mutation carriers. The prevalence of BRCA1 and BRCA2 mutations can vary in populations of different ethnicities which may contribute to variations in risk estimates. In Ashkenazi Jewish populations, mutations are substantially more prevalent (around 1 in 50 subjects) compared to non-Ashkenazi Jewish European populations (around 1 in 400 individuals). Germline BRCA1 and BRCA2 mutations are observed in all non-mucinous histologic subtypes of ovarian cancer but are most associated with the development of the high grade serous ovarian cancers, with around 15% patients of this histotype carrying a mutation in either gene.


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Several common, lower risk variants for ovarian cancer have been identified using population-based genome wide association studies (GWAS). Each risk variant is estimated to confer only modest increase in risk. Most risk variants identified so far are associated with high grade serous and/or all invasive epithelial ovarian cancers; but a few risk alleles have been shown to be specifically associated with a certain subtype. There is also evidence of pleiotropy, in which genetic variants in the same genomic region confer risk to two or more ovarian cancer subtypes. Most common variant risk alleles are located in the non-protein-coding DNA regions, suggesting that the likely functional mechanisms are through epigenomic regulation of one or more susceptibility gene targets.