Oleksii Nikolaienko

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.

Constitutional BRCA1 Epimutations: A Key for Understanding Basal‐Like Breast and High‐Grade Serous Ovarian Cancer

Germline pathogenic genetic variants in the BRCA1 and BRCA2 genes are the most frequent causes of familial breast and ovarian cancer. Contrasting BRCA2, epimutations in the BRCA1 gene are frequently detected in tissue from triple‐negative breast (TNBC) and high‐grade serous ovarian cancers (HGSOC). While studies over the last decade have reported BRCA1 epimutations in white blood cells (WBC) from breast and ovarian cancer patients, the potential hazard ratio for incident TNBC and HGSOC was not formally assessed until recently.Conducting a prospective nested case‐control study on women participating in the American Women’s Health Initiative Study, we provided firm evidence that mosaic WBC BRCA1 epimutations, even at allele frequencies < 0.1%, are associated with a significantly increased risk of both incident HGSOC and TNBC > 5 years after WBC collection. In a second study assessing BRCA1 epimutations in WBC and matched tumor samples from TNBC, our results indicated such epimutations to be the underlying cause of around 20% of TNBC, far exceeding the percentage of cases carrying BRCA1 germline pathogenic genetic variants.We detected primary constitutional BRCA1 epimutations in tissues derived from all three germ layers. They occur independently of BRCA1 promoter haplotypes but are present on the same allele in all WBC within affected individuals. Moreover, epimutations are consistently found on the same allele in normal and tumor breast tissue as well as in WBC. This finding, together with BRCA1 epimutations detected in WBC from newborns, strongly indicates an early embryonic event with clonal expansion affecting all germ layers.Future work in the field must lead to an understanding of exactly when and how the BRCA1 epimutations occur and, most importantly, whether primary constitutional epimutations in genes other than BRCA1 may cause an elevated risk of other cancer types.