[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-367180-105":59,"doc-detail-367180-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","defective-x-chromosome-inactivation-and-cancer-risk-in-women","Defective X-chromosome inactivation and cancer risk in women","","X-chromosome inactivation (XCI) compensates gene dosage differences in placental mammals, but XCI can be defective in a way that varies across individuals and cancer types in females. By using methylation levels of XCI-controlled genes, the study quantifies defective XCI and links reduced XIST expression and altered XCI-associated gene expression to increased female cancer risk. Defective XCI over 10% is attributable to 40% risk across 12 cancers, with validation in breast cancer showing higher triple-negative frequency, poorer survival, and chemotherapy-linked reduction.",{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/defective-x-chromosome-inactivation-and-cancer-risk-in-women/367180/",{"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/defective-x-chromosome-inactivation-and-cancer-risk-in-women/367180.png","ImageObject",300,407,{"name":92,"@type":93},"Oliver","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What does defective X-chromosome inactivation mean in this study?","Question",{"text":112,"@type":113},"Defective XCI refers to weakened maintenance of XCI control, reflected by consistent lowering of XIST expression and methylation changes in genes expected to stay silenced under XCI.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How is defective XCI measured?",{"text":117,"@type":113},"The study computes the percentage of 2-allele demethylation of CpGs in XCI regions, defining this as the X-chromosome reactivation (X-Ra) level.",{"name":119,"@type":110,"acceptedAnswer":120},"How does defective XCI relate to cancer outcomes in women?",{"text":121,"@type":113},"In breast cancer, defective XCI is associated with increased triple-negative subtype frequency and reduced survival, and it is linked to chemotherapy treatment effects in independent validations.","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},367180,1790508740,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},8796095461610,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","communications biology Article  \nA Nature Portfolio journal  \n[https://doi.org/10.1038/s42003-025-07691-y](https://doi.org/10.1038/s42003-025-07691-y)  \nDefective X-chromosome inactivation and cancer risk in women  \n Check for updates  \n\n| Alejandro Cáceres  1,2 , Luis A. Pérez-Jurado 3,4,5, Albert Alegret-García 1,2, Varun B. Dwaraka6, Ryan Smith6 & Juan R. González 1,2 |  |\n| --- | --- |\n| X-chromosome inactivation (XCI) is a fundamental mechanism in placental mammals that compensates for gene dosage differences between sexes. Using methylation levels of genes under XCI, we establish defective levels of XCI as a new source of interindividual variation among cancer types in females, characterized by a significant and consistent lowering of XIST expression and enrichment of differentially expressed genes under XCI. We show that defective XCI is an additive factor to the cancer risk of XCI escape deregulation in women. Defective XCI of more than 10% has an attributable risk of 40% among 12 different cancers from The Cancer Genome Atlas. Validations between independent studies of breast cancer samples show that defective XCI increases triplenegative subtype frequency, decreases survival rates, and is reduced by chemotherapy treatment. Mechanistically, it is associated with somatic mutations at TP53 and top MYC gains. In independent studies, defective XCI is detectable in blood and increases with aging, menopause, and cancer diagnosis. |  |\n| Background\u003Cbr>During early female development, one of the two X-chromosomes in each embryonic cell is randomly inactivated(Xi), leading to the formation ofBarr bodies, which are packed corpuscles in the cell nuclei that are visible under a microscope1. Chromosome X inactivation (XCI) thus achieves gene dosage compensation with males, who carry only one X-chromosome per cell2 and is a mechanism to avoid lethal consequences of X-chromosome aneuploidies. However, not all the genes in Xi undergo inactivation. Under normal conditions, some genes always escape XCI, whereas others appear to escape depending on the tissue3,4. It is estimated that up to 23% of X-linked genes can naturally escape inactivation4,5. In contrast, in some aggressive breast tumor cells, the entire Xi is lost, as evidenced by the loss of Barr bodies6. In certain cases, this Xi loss is accompanied by a duplication of the activated X-chromosome (Xa), leading to increased expression of X-linked genes7. Loss of XCI has been observed in other cancer cells; however, the extent to which complete or partial XCI loss is a feature of female cancer remains unknown8. Given that XCI levels vary among genes, cells9 and tissues4, it is likely that global XCI maintenance also varies among women. However, the lack of a quantitative measure that can assess the level of defective XCI maintenance in a bulk biological sample remains a significant barrier to evaluating the health risks associated with XCI loss in women. | XCI occurs early in development and is considered to be stably maintained throughout the cells and lifespan of females10. Facultative heterochromatin is regulated in Xi by XIST, which has important consequences for development and disease11. Histone modifications and DNA methylation are the main epigenetic modifications on Xi12. DNA methylation is a key factor for XCI maintenance6. In this study, we propose that a consequence of defective XCI is the loss of methylation of consistently silenced genes3,5. As such, we computed the percentage of 2-allele demethylation of CpGs inXCI regions as a metric of defective XCI frequency in a sample and called it X-chromosome reactivation (X-Ra) level. Using data from The Cancer Genome Atlas (TCGA), we demonstrated the global transcriptomic consequences ofX-Ra and determined its overarching role in female cancer. In breast cancer, we determined the molecular mechanisms likely driving the interindividual variations of X-Ra and validated its association with lower survival, tumor heterogeneity in t","cbCairgdDusQUUbL","https://ap.wps.com/l/cbCairgdDusQUUbL","pdf",2383054,13,"English","# Background\n# Defective XCI metric and study approach\n# Results\n## Study workflow\n## Methylation patterns in breast tissue samples","[{\"question\":\"What does defective X-chromosome inactivation mean in this study?\",\"answer\":\"Defective XCI refers to weakened maintenance of XCI control, reflected by consistent lowering of XIST expression and methylation changes in genes expected to stay silenced under XCI.\"},{\"question\":\"How is defective XCI measured?\",\"answer\":\"The study computes the percentage of 2-allele demethylation of CpGs in XCI regions, defining this as the X-chromosome reactivation (X-Ra) level.\"},{\"question\":\"How does defective XCI relate to cancer outcomes in women?\",\"answer\":\"In breast cancer, defective XCI is associated with increased triple-negative subtype frequency and reduced survival, and it is linked to chemotherapy treatment effects in independent validations.\"}]","Defective X-chromosome inactivation and cancer risk in women | PDF",1790169622,33]