Heritable DNA methylation marks associated with prostate cancer risk.

The currently identified genetic prostate cancer risk factors account for less than 40% of the familial risk for the disease. Very few of these genetic risk factors are able to predict the risk of aggressive disease. The identification of further biomarkers and risk factors that can predict risk and the clinical outcome for prostate cancer could both improve prevention, early diagnosis of potentially aggressive and lethal cases, and reduce overtreatment of indolent disease. We have been working to identify some of the missing heritability of prostate cancer by considering non-genetic heritable risk factors. DNA methylation marks in peripheral blood can act in analogous ways to germline genetic variants in regard to cancer predisposition but they have yet to be systematically assessed as risk factors for prostate cancer. We have published work that applied an innovative, statistical genetic method to identify heritable methylation marks associated with breast and prostate cancer risk. We identified 41 DNA methylation marks associated with heritable prostate cancer risk. Heritable methylation marks thus must account for some of the familial risk of prostate cancer and the integration of epigenetic testing into current genetic testing regimes offers considerable opportunities for identifying more of the men who are at high risk of developing prostate cancer by placing each man more precisely on the prostate cancer risk spectrum. This project will explore alternative approaches to the identification of heritable methylation marks associated with prostate cancer risk including taregtted gene panel sequencing. The project will also explore the relationship between these heritable methylation marks, genetic variation (rare and common variants), other prostate cancer risk factors and the corresponding tumour phenotypes. The project will advance work towards incorporating this new information into the current (predominantly) genetic tests for prostate cancer predisposition.