Heritable genomic risk factors for prostate cancer.

Known genetic risk factors for prostate cancer include rare genetic variants in prostate cancer predisposition genes that are associated with high to moderate prostate cancer risk and an increasing number of common genetic variants each associated with very small increments in cancer risk. Men in the highest 1% of the polygenic risk score (PRS) distribution (sum of the log odds ratios for each common risk-associated variant) for prostate cancer are at a 6-fold increased risk. These genetic risk factors combine to create a wide spectrum of genetic risk for prostate cancer. However, the currently identified genetic risk factors account for approximately half of the familial risk for prostate cancer. We have applied whole genome massively parallel sequencing to highly-selected multiple-case prostate cancer families. Early analyses of These whole genome sequences has been focused on the coding and flanking intronic regions of recognised genes. We have identified a very small number of families carry pathogenic genetic variants in genes already known to be associated with prostate cancer predisposition (e.g. BRCA2). This project will conduct work to further consider large genomic structural variants, including copy number variants, using the whole genome data from participating families. Further work will involve expanding the analysis to population-based samples of prostate cancer families to validate findings and estimate the disease penetrance of structural variants. The project will involve laboratory based work applying state-of-the-art molecular genetic analyses including massively parallel sequencing and apply a number of bioinformatics approaches to data analyses. Success of our project will provide the evidence base from which clinical cancer genetics services can improve personalized clinical management for men at high risk of aggressive prostate cancer.