Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors?

Constitutional epimutations are epigenetic aberrations that arise in normal cells prenatally. Two major forms exist: secondary constitutional epimutations (SCEs), associated with cis-acting genetic aberrations, and primary constitutional epimutations (PCEs), for which no associated genetic aberrations were identified. Some SCEs have been associated with risk of cancer (MLH1 and MSH2 with colon or endometrial cancers, BRCA1 with familial breast and ovarian cancers), although such epimutations are rare, with a total of <100 cases reported. This contrasts recent findings for PCE, where low-level mosaic BRCA1 epimutations are recorded in 5%-10% of healthy females across all age groups, including newborns. BRCA1 PCEs predict an elevated risk of high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) and are estimated to account for about 20% of all TNBCs. A similarly high population frequency is observed for mosaic constitutional epimutations in MGMT, occurring as PCE or SCE, but not in MLH1. Contrasting BRCA1 and MLH1, a potential association with cancer risk for MGMT epimutations is yet unclear. In this review, we provide a summary of findings linking constitutional epimutations to cancer risk with emphasis on PCE. We also highlight challenges in detection of PCE exemplified by low-level mosaic epimutations in BRCA1 and indicate the need for further studies, hypothesizing that improved knowledge about PCE may add significantly to our understanding of cancer risk, carcinogenesis, and potentially development of other diseases as well.