[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-340598-105":59,"doc-detail-340598-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","recurrent-disruption-of-tumour-suppressor-genes-in-cancer-by-somatic-mutations-in-cleavage-and-polyadenylation-signals","Recurrent disruption of tumour suppressor genes in cancer by somatic mutations in cleavage and polyadenylation signals","","The expression of eukaryotic genes depends on precise 3'-terminal cleavage and polyadenylation of pre-mRNA transcripts, and defects in these processes contribute to cancer and other diseases. This study analyzes somatic mutations affecting 3'UTR polyadenylation signals in human cancers using the PCAWG dataset. It identifies a strong enrichment of cancer-specific mutations disrupting evolutionarily conserved cleavage/polyadenylation signals within tumour suppressor genes. Further bioinformatics and experimental work indicates these mutations can downregulate tumour suppressor gene expression, implicating a novel noncoding driver class.",{"@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/recurrent-disruption-of-tumour-suppressor-genes-in-cancer-by-somatic-mutations-in-cleavage-and-polyadenylation-signals/340598/",{"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/recurrent-disruption-of-tumour-suppressor-genes-in-cancer-by-somatic-mutations-in-cleavage-and-polyadenylation-signals/340598.png","ImageObject",300,407,{"name":92,"@type":93},"Clementine","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-22","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What biological process does the study focus on?","Question",{"text":112,"@type":113},"It focuses on the 3'-terminal cleavage and polyadenylation of pre-mRNA and how polyadenylation signals (PAS) are regulated.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How did the researchers identify relevant mutations in cancer?",{"text":117,"@type":113},"They systematically analyzed somatic mutations affecting 3'UTR polyadenylation signals across human cancers using the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the key finding about tumour suppressor genes?",{"text":121,"@type":113},"Cancer-specific somatic mutations disrupting evolutionarily conserved cleavage/polyadenylation signals are enriched in tumour suppressor genes and can downregulate their expression.","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},340598,1790117130,{"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":29,"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":36},1374391974564,"https://ap-avatar.wpscdn.com/avatar/14000253aa45c000a9e?x-image-process=image/resize,m_fixed,w_180,h_180&k=1779874745381141002","RESEARCH ARTICLE  \n*For correspondence:  \n[yaroslav.kainov@kcl.ac.uk](yaroslav.kainov@kcl.ac.uk) (YK); [eugene.makeyev@kcl.ac.uk](eugene.makeyev@kcl.ac.uk)[ ](eugene.makeyev@kcl.ac.uk)(EVM)  \nCompeting interest: The authors declare that no competing interests exist.  \nFunding: See page 14  \nSent for Review  \n24 June 2024  \nPreprint posted  \n28 June 2024  \nReviewed preprint posted  \n22 August 2024  \nReviewed preprint revised  \n13 November 2024  \nVersion of Record published  \n11 December 2024  \nReviewing Editor: Murim Choi, Seoul National University, Republic of Korea  \n Copyright Kainov et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use andredistribution provided that the original author and source are credited.  \nRecurrent disruption of tumour suppressor genes in cancer by somatic mutations in cleavage and polyadenylation signals  \nYaroslav Kainov1,2*, Fursham Hamid1, Eugene V Makeyev1*  \n1Centre for Developmental Neurobiology, King’s College London, London, United Kingdom; 2 Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom  \n\n| eLife Assessment\u003Cbr>This important study substantially advances our understanding of noncoding somatic mutations by identifying a novel class of mutations that affect 3'UTR polyadenylation signals enriched in tumor suppressor genes in cancer. The evidence supporting the conclusions is convincing, with rigorous statistical analyses. The work will be of broad interest to cancer researchers. |\n| --- |\n| Abstract The expression of eukaryotic genes relies on the precise 3'-terminal cleavage and polyadenylation of newly synthesized pre-mRNA transcripts. Defects in these processes have been associated with various diseases, including cancer. While cancer-focused sequencing studies have identified numerous driver mutations in protein-coding sequences, noncoding drivers – particularly those affecting the cis-elements required for pre-mRNA cleavage and polyadenylation – have received less attention. Here, we systematically analysed somatic mutations affecting 3'UTR polyadenylation signals in human cancers using the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset. We found a striking enrichment of cancer-specific somatic mutations that disrupt strong and evolutionarily conserved cleavage and polyadenylation signals within tumour suppressor genes. Further bioinformatics and experimental analyses conducted as a part of our study suggest that these mutations have a profound capacity to downregulate the expression of tumour suppressor genes. Thus, this work uncovers a novel class of noncoding somatic mutations with significant potential to drive cancer progression. |\n\nIntroduction  \nMost eukaryotic mRNAs are modified by the addition of a 5’-terminal 7-methylguanosine cap, splicing of intronic sequences, and 3'-terminal cleavage and polyadenylation. The cleavage and polyadenylation reactions are tightly coupled with transcription termination and the release of newly synthesized transcripts from RNA polymerase II. Therefore, precise cleavage and polyadenylation are critical for the production of mature mRNAs. Mechanistically, these reactions require a co-transcriptional assembly of a multisubunit protein complex at the corresponding cis-regulatory sequences near the pre-mRNA cleavage site (CS) (Tian and Manley, 2017; Neve et al., 2017; Shi et al., 2009). A key ciselement guiding the assembly of the cleavage and polyadenylation machinery is the polyadenylation signal (PAS) . The most common PAS sequences in mammals are AATAAA and ATTAAA hexamers,  \nKainov et al. eLife 2024;13:RP99040. DOI: [https://doi.org/10.7554/eLife.99040](https://doi.org/10.7554/eLife.99040) 1 of 16  \n Research article Cancer Biology | Genetics and Genomics  \nalthough their single nucleotide-substituted variants may function in some cases (Proudfoot, 1991; Beaudoing et al., 2000) .  \nEarlier studies have emphasized the importa","cbCaisAApRdrNfiF","https://ap.wps.com/l/cbCaisAApRdrNfiF","pdf",4308445,16,"English","# Introduction\n## Pre-mRNA cleavage and polyadenylation in gene expression\n## Polyadenylation signals (PAS) and their cis-elements\n## Prior work and the gap for somatic PAS mutations in cancer\n## Genome-wide cancer sequencing and focus on noncoding drivers\n# Results (eLife Assessment and Abstract summary)","[{\"question\":\"What biological process does the study focus on?\",\"answer\":\"It focuses on the 3'-terminal cleavage and polyadenylation of pre-mRNA and how polyadenylation signals (PAS) are regulated.\"},{\"question\":\"How did the researchers identify relevant mutations in cancer?\",\"answer\":\"They systematically analyzed somatic mutations affecting 3'UTR polyadenylation signals across human cancers using the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset.\"},{\"question\":\"What is the key finding about tumour suppressor genes?\",\"answer\":\"Cancer-specific somatic mutations disrupting evolutionarily conserved cleavage/polyadenylation signals are enriched in tumour suppressor genes and can downregulate their expression.\"}]","Recurrent disruption of tumour suppressor genes in cancer by somatic mutations in cleavage and polyadenylation signals | PDF",1790037598]