[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-381046-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-381046-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","pan-cancer-association-of-dna-repair-deficiencies-with-whole-genome-mutational-patterns","Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns","","DNA repair deficiencies in cancers can generate characteristic, genome-wide mutational patterns, exemplified by BRCA1/2 loss and PARP inhibitor response prediction. The study trains and evaluates predictive models for loss-of-function (LOF) in 145 DNA damage response genes using whole-genome mutational patterns, including structural variants, indels, and base-substitution signatures. It identifies 24 genes with accurate deficiency prediction, including expected patterns for BRCA1/2, MSH3/6, TP53, and CDK12. The work demonstrates prostate-cancer enrichment for CDK12 LOF via tandem duplications, reports novel associations for several additional genes, and compiles predictive models for target discovery and therapy guidance.",{"@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/pan-cancer-association-of-dna-repair-deficiencies-with-whole-genome-mutational-patterns/381046/",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/pan-cancer-association-of-dna-repair-deficiencies-with-whole-genome-mutational-patterns/381046.png","ImageObject",300,407,{"name":42,"@type":43},"Hazel","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-01","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What data and genomic features are used to predict DNA damage response gene deficiency?","Question",{"text":63,"@type":64},"The models are trained on genome-wide mutational patterns, including structural variants, indels, and base-substitution signatures.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How many DNA damage response genes and what type of variants are modeled?",{"text":68,"@type":64},"Predictive models are built for loss-of-function (LOF) of 145 DNA damage response genes.",{"name":70,"@type":61,"acceptedAnswer":71},"What does the study show about CDK12 deficiency in prostate cancer?",{"text":72,"@type":64},"CDK12 LOF is associated with tandem duplications, and the study demonstrates that this association can accurately predict gene deficiency in prostate cancers.","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},381046,1790293483,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,114,119,122,126],{"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":55,"doc_module":4,"doc_module_name":25,"category_name":111,"show_sort_weight":112,"slug":113},"Research & Report",30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"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":145},137441390410,"https://ap-avatar.wpscdn.com/avatar/2000252f4ab5702993?_k=1776741390130283984","ReSeARCH ARtICLe  \n*For correspondence:  \n[eva@sund.ku.dk](eva@sund.ku.dk) (eRH);  \n[jakob.skou@clin.au.dk](jakob.skou@clin.au.dk) (JSkouP)  \nCompeting interest: The authors declare that no competing interests exist.  \nFunding: See page 21  \nPreprinted: 03 February 2022  \nReceived: 20 June 2022  \nAccepted: 26 February 2023  \nPublished: 08 March 2023  \nReviewing Editor: W Kimryn Rathmell, Vanderbilt University Medical Center, United States  \n Copyright Sørensen 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.  \nPan-cancer association of DNA repair deficiencies with whole-genome mutational patterns  \nSimon Grund Sørensen1,2, Amruta Shrikhande3, Gustav Alexander Poulsgaard1,2, Mikkel Hovden Christensen1,2, Johanna Bertl1,2, Britt Elmedal Laursen1,2,4, Eva R Hoffmann3*, Jakob Skou Pedersen1,2,5*  \n1 Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark; 2 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3 DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark; 4 Department of Biomedicine, Aarhus University, Aarhus, Denmark; 5 Bioinformatics Research Center (BiRC), Aarhus University, Aarhus, Denmark  \n\n| Abstract DNA repair deficiencies in cancers may result in characteristic mutational patterns, as exemplified by deficiency of BRCA1/2 and efficacy prediction for PARP inhibitors. We trained and evaluated predictive models for loss-of-function (LOF) of 145 individual DNA damage response genes based on genome-wide mutational patterns, including structural variants, indels, and basesubstitution signatures. We identified 24 genes whose deficiency could be predicted with good accuracy, including expected mutational patterns for BRCA1/2, MSH3/6, TP53, and CDK12 LOF variants. CDK12 is associated with tandem duplications, and we here demonstrate that this association can accurately predict gene deficiency in prostate cancers (area under the receiver operator characteristic curve = 0.97) . Our novel associations include mono-or biallelic LOF variants of ATRX, IDH1, HERC2, CDKN2A, PTEN, and SMARCA4, and our systematic approach yielded a catalogue of predictive models, which may provide targets for further research and development of treatment, and potentially help guide therapy. |\n| --- |\n| Editor's evaluation\u003Cbr>This is a well-motivated study looking at the association of DNA repair deficiencies with mutational patterns. This study is of interest to the cancer genomics community and highlights how the understanding of DNA repair processes can be used in the development of novel cancer therapy, andwill also be of interest to researchers in the field of genomic medicine and cancer mutagenesis. It presents predictive models with potential clinical applications that can identify patients with specific gene dysfunction based on characteristic patterns of mutation. The key findings are well supported. |\n\nIntroduction  \nThe DNA damage response (DDR) and repair pathways are central to the genetic integrity of cells, and deficiencies may cause mutational patterns genome-wide (Lindahl, 1993; Nik-Zainal et al., 2012; Volkova et al., 2020) . Some DNA repair deficiencies are known to modulate the response to therapies: BRCA1/2 deficiency renders cancers susceptible to treatment with PARP inhibitors (Bryant et al., 2007), mismatch repair (MMR)-deficient cancers are sensitive to checkpoint inhibitors (Leet al., 2015) but resistant to alkylating agents such as temozolamide (von Bueren et al., 2012), and  \nSørensen et al. eLife 2023;12:e81224. DOI: [https://doi.org/10.7554/eLife.81224](https://doi.org/10.7554/eLife.81224) 1 of 27  \n Research article Cancer Biology | Computational and Systems Biology  \neLife digest Many different aspects of the environment – such as ultraviolet rad","cbCaimzidLcTM674","https://ap.wps.com/l/cbCaimzidLcTM674","pdf",2813301,27,"English","# Abstract\n# Editor's evaluation\n# Introduction\n# eLife digest","[{\"question\":\"What data and genomic features are used to predict DNA damage response gene deficiency?\",\"answer\":\"The models are trained on genome-wide mutational patterns, including structural variants, indels, and base-substitution signatures.\"},{\"question\":\"How many DNA damage response genes and what type of variants are modeled?\",\"answer\":\"Predictive models are built for loss-of-function (LOF) of 145 DNA damage response genes.\"},{\"question\":\"What does the study show about CDK12 deficiency in prostate cancer?\",\"answer\":\"CDK12 LOF is associated with tandem duplications, and the study demonstrates that this association can accurately predict gene deficiency in prostate cancers.\"}]","Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns | PDF",1790243288,68]