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Some SCEs have been associated with risk of cancer (\n            <jats:italic>MLH1<\/jats:italic>\n            and\n            <jats:italic>MSH2<\/jats:italic>\n            with colon or endometrial cancers,\n            <jats:italic>BRCA1<\/jats:italic>\n            with familial breast and ovarian cancers), although such epimutations are rare, with a total of &lt;100 cases reported. This contrasts recent findings for PCE, where low-level mosaic\n            <jats:italic>BRCA1<\/jats:italic>\n            epimutations are recorded in 5%-10% of healthy females across all age groups, including newborns.\n            <jats:italic>BRCA1<\/jats:italic>\n            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\n            <jats:italic>MGMT<\/jats:italic>\n            , occurring as PCE or SCE, but not in\n            <jats:italic>MLH1<\/jats:italic>\n            . Contrasting\n            <jats:italic>BRCA1<\/jats:italic>\n            and\n            <jats:italic>MLH1<\/jats:italic>\n            , a potential association with cancer risk for\n            <jats:italic>MGMT<\/jats:italic>\n            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\n            <jats:italic>BRCA1<\/jats:italic>\n            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.\n          <\/jats:p>","DOI":"10.1200\/po-24-00746","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T21:57:01Z","timestamp":1743717421000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":4,"title":["Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors?"],"prefix":"10.1200","author":[{"given":"Per Eystein","family":"L\u00f8nning","sequence":"first","affiliation":[{"name":"Department of Oncology, Haukeland University Hospital, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5910-4934","authenticated-orcid":true,"given":"Oleksii","family":"Nikolaienko","sequence":"additional","affiliation":[{"name":"Department of Oncology, Haukeland University Hospital, Bergen, Norway"},{"name":"Department of Clinical Science, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4153-1655","authenticated-orcid":true,"given":"Stian","family":"Knappskog","sequence":"additional","affiliation":[{"name":"Department of Oncology, Haukeland University Hospital, Bergen, Norway"},{"name":"Department of Clinical Science, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00672-8"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2021.6987"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.03.001"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/85.22.1819"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001648-199503000-00017"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-018-4444-0"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(02)00496-3"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)05526-8"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(07)70377-7"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canep.2014.07.004"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu214"},{"key":"e_1_3_5_13_2","first-page":"3225","article-title":"A gene hypermethylation profile of human cancer","volume":"61","author":"Esteller M","year":"2001","unstructured":"Esteller M, Corn PG, Baylin SB, et al: A gene hypermethylation profile of human cancer. 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