[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-368381-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-368381-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","constitutional-epimutations-from-rare-events-toward-major-cancer-risk-factors-review-article","Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors? - Review Article","","Constitutional epimutations are prenatal epigenetic aberrations in normal cells, present as two main types: secondary constitutional epimutations linked to cis-acting genetic aberrations, and primary constitutional epimutations without identified genetic correlates. Some secondary forms are tied to cancer risk but remain extremely rare (\u003C100 cases). In contrast, low-level mosaic BRCA1 primary constitutional epimutations occur in 5%-10% of healthy females and predict elevated high-grade serous ovarian cancer and triple-negative breast cancer risk.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/constitutional-epimutations-from-rare-events-toward-major-cancer-risk-factors-review-article/368381/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/constitutional-epimutations-from-rare-events-toward-major-cancer-risk-factors-review-article/368381.png","ImageObject",300,407,{"name":42,"@type":43},"Margaret","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",10,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What are constitutional epimutations and when do they arise?","Question",{"text":63,"@type":64},"Constitutional epimutations are epigenetic aberrations found in normal cells that arise prenatally.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How do primary and secondary constitutional epimutations differ?",{"text":68,"@type":64},"Secondary constitutional epimutations (SCEs) are associated with cis-acting genetic aberrations, while primary constitutional epimutations (PCEs) show no associated genetic aberrations identified.",{"name":70,"@type":61,"acceptedAnswer":71},"Which constitutional epimutations are linked to elevated cancer risk in the review?",{"text":72,"@type":64},"Low-level mosaic BRCA1 PCEs predict elevated risk of high-grade serous ovarian cancer and triple-negative breast cancer, and they are estimated to account for about 20% of all TNBCs.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},368381,1790900018,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":55,"slug":125},"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":113},137451207643,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Review Articles  \nConstitutional Epimutations: From Rare Events Toward Major  \nCancer Risk Factors?  \nPer Eystein Lønning, MD, PhD1; Oleksii Nikolaienko, PhD1,2 ; and Stian Knappskog, PhD1,2  DOI [https://doi.org/10.1200/PO-24-00746](https://doi.org/10.1200/PO-24-00746)  \nABSTRACT  \nConstitutional epimutations are epigenetic aberrations that arise in normal cells prenatally. Two major forms exist: secondary constitutional epimutations (SCEs), associated with cisacting 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 \u003C100 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 inMGMT, occurring as PCE or SCE, but not in MLH1 . Contrasting BRCA1 and MLH1 , a potential association with cancer risk for MGMTepimutations 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 PCEmayadd significantly to our understanding of cancer risk, carcinogenesis, and potentially development of other diseases as well.  \nAccepted January 14, 2025 Published April 3, 2025  \nJCO Precis Oncol 9:e2400746 © 2025 by American Society of Clinical Oncology  \nCreative Commons Attribution Non-Commercial No Derivatives 4.0 License  \nINTRODUCTION  \nThe incidence of most cancer forms is increasing worldwide.1 ,2 Although lifestyle factors including occupational exposure to toxic agents, dietary habits, alcohol, and other factors have all been associated with cancer risk,2 the exact roles of individual factors as well as the mechanism by which they execute their effects remain incompletely understood. Some toxic agents (such as cigarette smoking and ultraviolet light exposure) are associated with distinct genomic signatures in certain cancer forms such as lung cancer and melanomas3 ; however, for most cancer forms, defined mutational signatures related to exogenous agents have not been identified. Although cancer risk increases with aging, carcinogenesis evolves over time, and indirect evidence, including immigration studies from different countries revealing a strong impact on cancer risk in second-generation immigrants,4-7 points toward early-life, potentially prenatal events to be of importance.8-11  \nCancers are predominantly characterized by their genomic aberrations, but over the past decades, there has also been an increasing focus on epigenetic alterations in cancer biology.12-15 Although epimutations are frequently observed in cancers, an unresolved question has been to what extent  \nearly epimutations in healthy tissue may be cancer risk factors. Elucidating such a role for epimutations may have significant implications to our understanding of the underlying biology of carcinogenesis.  \nEPIMUTATIONS  \nAn extensive description of the mechanisms governing epigenetic regulation is not the subject of this review, and the readers are referred to other contemporary sources.16,17 As gene promoter hypermethylation and histone modulation hindering transcription often appear in concert,18 and since promoter hypermethylation is the epigenetic mechanism, most extensively characterized in human cancers, here, we will use the term epimutation synonym","cbCaijoZPZP8HQWx","https://ap.wps.com/l/cbCaijoZPZP8HQWx","pdf",1016837,12,"English","# Abstract\n# Introduction\n# Epimutations\n# Constitutional Epimutations","[{\"question\":\"What are constitutional epimutations and when do they arise?\",\"answer\":\"Constitutional epimutations are epigenetic aberrations found in normal cells that arise prenatally.\"},{\"question\":\"How do primary and secondary constitutional epimutations differ?\",\"answer\":\"Secondary constitutional epimutations (SCEs) are associated with cis-acting genetic aberrations, while primary constitutional epimutations (PCEs) show no associated genetic aberrations identified.\"},{\"question\":\"Which constitutional epimutations are linked to elevated cancer risk in the review?\",\"answer\":\"Low-level mosaic BRCA1 PCEs predict elevated risk of high-grade serous ovarian cancer and triple-negative breast cancer, and they are estimated to account for about 20% of all TNBCs.\"}]","Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors? - Review Article | PDF",1790176635]