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Contrasts established roles of BRCA1 epimutations in triple-negative breast cancer with evidence that a minor fraction of ER+ tumors may originate from BRCA1-epimutated subclones. Explains mosaic constitutional epimutations affecting \u003C1% of cells and argues that clonal epimutations in tumors strongly suggest BRCA1 deficiency drives tumor evolution, positioning these cancers as tools to study BRCA1-driven mechanisms.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/estrogen-receptor-positive-brca1-deficient-breast-cancer-brca1-epimutated-tumors-presenting-a-piece-to-the-puzzle/345520/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/estrogen-receptor-positive-brca1-deficient-breast-cancer-brca1-epimutated-tumors-presenting-a-piece-to-the-puzzle/345520.png","ImageObject",300,407,{"name":92,"@type":93},"Levi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How are BRCA1 pathogenic variants associated with triple-negative vs estrogen receptor-positive breast cancer?","Question",{"text":112,"@type":113},"BRCA1 germline pathogenic variants strongly increase hazard for triple-negative breast cancer, while also producing a moderately elevated risk for estrogen receptor-positive breast cancer.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What role do BRCA1 epimutations (promoter hypermethylation) play in triple-negative breast cancer?",{"text":117,"@type":113},"BRCA1 epimutations are identified as a major factor in triple-negative breast cancer, with a substantial proportion showing clonal epimutations and evidence of tumor origins from small normal-cell subclones.",{"name":119,"@type":110,"acceptedAnswer":120},"Why do constitutional BRCA1 epimutations and clonal tumor epimutations matter for understanding tumorigenesis?",{"text":121,"@type":113},"Constitutional epimutations are mosaic, affecting typically \u003C1% of cells, whereas fully clonal epimutations in tumors suggest BRCA1 deficiency as an underlying cause of tumor evolution rather than a passenger event.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},345520,1790197493,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":39,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":46},7971461740909,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Lønning etal. Breast Cancer Research (2026) 28:103 Breast Cancer Research  \n[https://doi.org/10.1186/s13058-026-02279-8](https://doi.org/10.1186/s13058-026-02279-8)  \nPERSPECTIVE Open Access  \nEstrogen receptor-positive, BRCA1-deficient breast cancer: BRCA1-epimutated tumors presenting a piece to the puzzle  \nPer E. Lønning 1*, Oleksii Nikolaienko1,2 and Stian Knappskog1,2  \nAbstract  \nWhile the majority of breast cancers arising in women with germline BRCA1 pathogenic variants (gBRCA1) are triplenegative (TNBC), these women also have a moderately increased risk of ER+ breast cancers. The contribution of BRCA1 deficiency to the development of ER+ breast cancers in gBRCA1 carriers is incompletely understood. BRCA1 epimutations (promoter hypermethylation) have emerged as a major factor in TNBC. About 25–30% of all TNBCs harbor clonal BRCA1 epimutations. In the majority of these patients, the tumor seems to arise from small subclones of normal cells harboring constitutional BRCA1 epimutations. Mirroring findings for gBRCA1 carriers, a minor fraction of ER+ breast cancers seems to arise from BRCA1 epimutated subclones as well. An important difference between normal cells in individuals harboring gBRCA1 pathogenic variants and BRCA1 constitutional epimutations is that constitutional epimutations are mosaic, most often affecting \u003C 1% of an individual’s cells. Considering cancers arising in gBRCA1 carriers, where all cells of the individual are affected, in some cases BRCA1 deficiency may be of limited importance to the tumorigenesis; the BRCA1 variants could be passenger events only. In contrast, the fact that women harboring constitutional epimutations in a small fraction of normal cells have increased risk of developing a TNBC harboring fully clonal BRCA1 epimutations strongly suggest BRCA1 deficiency to be an underlying cause in the tumor evolution. Most likely, the same argument applies to ER+ tumors harboring clonal BRCA1 epimutations, making these cancers valuable tools exploring the role of BRCA1 deficiency in development of ER+ breast cancers.  \nKeywords Breast cancer, Triple-negative breast cancer, BRCA1, Epimutation, Constitutional epimutation, Estrogen receptor  \n*Correspondence:  \nPer E. Lønning  \n[per.lonning@helse-bergen. no](per.lonning@helse-bergen. no)  \n1Cancer Clinic, Haukeland University Hospital, Bergen, Norway 2Department of Clinical Science, University of Bergen, Bergen, Norway  \n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.)  \nLønning et al. Breast Cancer Research (2026) 28:103  \nIntroduction  \nGermline pathogenic variants (gPVs) in BRCA1 are associated with a 43–55 fold increased hazard ratio (HR) for developing triple-negative breast cancer (TNBC); in addition, they also confer a moderately elevated HR of 3-3.5 for estrogen receptor-positive (ER+) breast cancer (BC)[1, 2]. Given the higher incidence of ER+ BC, this translates into ","cbCaioEI0O73jsHu","https://ap.wps.com/l/cbCaioEI0O73jsHu","pdf",1722469,"English","# Abstract\n# Introduction\n## Germline BRCA1 variants and ER+ vs TNBC incidence\n## Epimutations and tumor evolution concepts\n## Biological characteristics of ER+ BRCA1-deficient breast cancer","[{\"question\":\"How are BRCA1 pathogenic variants associated with triple-negative vs estrogen receptor-positive breast cancer?\",\"answer\":\"BRCA1 germline pathogenic variants strongly increase hazard for triple-negative breast cancer, while also producing a moderately elevated risk for estrogen receptor-positive breast cancer.\"},{\"question\":\"What role do BRCA1 epimutations (promoter hypermethylation) play in triple-negative breast cancer?\",\"answer\":\"BRCA1 epimutations are identified as a major factor in triple-negative breast cancer, with a substantial proportion showing clonal epimutations and evidence of tumor origins from small normal-cell subclones.\"},{\"question\":\"Why do constitutional BRCA1 epimutations and clonal tumor epimutations matter for understanding tumorigenesis?\",\"answer\":\"Constitutional epimutations are mosaic, affecting typically \\u003c1% of cells, whereas fully clonal epimutations in tumors suggest BRCA1 deficiency as an underlying cause of tumor evolution rather than a passenger event.\"}]","Estrogen receptor-positive, BRCA1-deficient breast cancer: BRCA1-epimutated tumors presenting a piece to the puzzle | PDF",1790057958]