According to US Surveillance, Epidemiology, and End Results (SEER), overall, the five year survival rate for ovarian cancer is 49%, however for those aged 15-39 the survival rate is 81% and declines steadily with age; 65-74 year olds having a 41% five year survival rate. Variants in certain high risk genes have been found to predict the development of epithelial ovarian cancer (EOC). These genes, however, only account for half of the genetic risk of EOC, possibly due to the difficulty of detecting combinatorial risk effects generated from multiple genes.
Paul Pharoah of University of Cambridge, UK, and colleagues, aimed to identify additional ovarian cancer susceptibility genes using case-control sequencing of candidate genes. For targeted sequencing 5,914 EOC cases and 5,479 controls with European ancestries from 19 studies, 1 familial ovarian cancer study from Poland, 2 clinical trials and 3 case only studies were inputs. To extract exome sequencing data 829 cases and 913 controls from two ovarian cancer case-control studies were used. OncoArray and UK Biobank Axiom Array were used for confirmation. The results were published in the Journal of Medical Genetics.
There were higher frequencies of mutations in ovarian cancer genes POLK, PALB2 and SLX4 and a lower frequency of mutations in FBXO10. When combining all datasets, including UK Biobank, only PALB2 remained a likely true risk association following Bayes false discovery probability analysis. Certain missense variants in DUOX1, PAK4, and FANCE classified as deleterious also appeared to be weakly associated with ovarian cancer.
The study indicates that PALB2 mutations should be taken seriously as a candidate for risk assessment of ovarian cancer, however, the confidence intervals were large meaning further very large, well-designed case-control studies are needed to provide more accurate risk assessment, which would be suitable for use in clinical counselling.
“In summary, we have found relatively strong evidence that deleterious germline mutations in PALB2 are associated with a moderate increase in the risk of [high-grade serous ovarian cancer] with weak evidence for POLK, SLX4 and FBXO10. Mutations in the other 50 genes we tested are unlikely to contribute meaningfully to genetic predisposition to [high-grade serous ovarian cancer]. This study highlights the importance of large sample sizes needed to obtain risk estimates with the precision necessary for clinical use,” concluded the authors.