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. Notably, prostate cancers arising in men who carry pathogenic variants in BRCA1 and BRCA2 are more commonly aggressive, have increased nodal involvement, metastases and are associated with poorer survival. However, the frequency of these pathogenic mutations in men (under age 55 years) affected with prostate cancer is only 2%. Currently, the vast majority of men undergoing genetic testing in “high risk” clinical genetic services receive an uninformative (negative) test result. 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. For example, intergenerational transmission of methylation marks has been observed in MLH1 and MSH2 in the context of Lynch Syndrome. Lynch Syndrome is an hereditary condition, where genetic mutations in mismatch repair genes predispose individuals to colorectal, endometrial and other cancers. While two thirds of Lynch Syndrome cases carry germline genetic mutations in the DNA mismatch genes, a small proportion of Lynch Syndrome has been associated with heritable methylation marks. Some methylation marks at MLH1 and MSH2 are linked to nearby cis-acting genetic variants and consequently follow Mendelian inheritance patterns. Other methylation marks at MLH1 have not been linked to underlying genetic variations. We have recently published work that applied an innovative, statistical genetic method to identify heritable methylation marks associated with breast cancer risk. This ground-breaking work was achieved using a statistical method developed from genetic segregation analysis, DNA methylation measured using high density methylation arrays and a multiple breast cancer case family design. With support from a Novel Concept Award from the Prostate Cancer Foundation of Australia we conducted a multiple-case prostate cancer family study and identified 41 DNA methylation marks associated with heritable prostate cancer risk. Heritable methylation marks thus must also 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 whole genome bisulphite 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.
Prostate cancer, heritable cancer risk, familial cancer, epigenomics, genomics, bioinformatics, risk prediction
School of Clinical Sciences at Monash Health / Hudson Institute of Medical Research
Masters by research
Top-up scholarship funding available
Monash Medical Centre Clayton