The currently identified genetic cancer risk factors account for less than 50% of the breast cancer familial risk and less than 40% of the prostate cancer familial risk. The vast majority of people undergoing genetic testing in “high risk” clinical genetic services receive an uninformative test result.
Constitutional DNA methylation can mimic the effect of a germline genetic mutation and result in gene silencing. There have been some reports of Mendelian-like inheritance of germline DNA methylation in known cancer susceptibility genes. For instance, individuals with MLH1 silenced throughout the soma fit the clinical criteria for hereditary nonpolyposis colorectal cancer that is indistinguishable from the syndrome resulting from germline mutations in MLH1. Family clustering of cancer could therefore be due to epigenetic as well as genetic and shared environmental factors.
We have identified heritable methylation marks associated with breast and/or prostate cancer susceptibility by conducting a study of Australian multi-generational families with multiple cases of breast or prostate cancer who are not known to carry genetic mutations in cancer susceptibility genes. We developed and applied a new statistical method to identify heritable methylation marks based on complex segregation analysis and identified methylation marks significantly associated with breast and/or prostate cancer risk. Several marks across VTRNA2-1, a gene located in a differentially methylated region that is involved in imprinting and shows allele-specific methylation, were associated with heritable risk of both cancer types.
A proportion of all identified marks were found to be associated with cancer risk in independent nested case-control studies of cancer (ie outside of the multiple-case family setting). Identifying a new class of heritable cancer risk factor provides opportunities to increase the precision of tools aimed at identifying those at greatest risk of the disease, enabling precision cancer prevention.