[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-385523-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-385523-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-clinical-impact-of-latent-drivers-from-double-mutations","Pan-cancer clinical impact of latent drivers from double mutations","","Pan-cancer analysis identifies rare “latent driver” mutations in cancer genomes and evaluates their clinical relevance when present as same-gene double mutations. Comprehensive statistical screening of ~60,000 tumor sequences from TCGA and AACR-GENIE reveals 155 co-occurring same-gene double mutations, with 140 components cataloged as latent drivers. Cell line and patient-derived xenograft drug-response data show that in specific genes, double mutations can markedly increase oncogenic activity and improve drug response, exemplified by PIK3CA. The rarity of doublets is discussed as a consequence of oncogene-induced senescence and background mutational load.",{"@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-clinical-impact-of-latent-drivers-from-double-mutations/385523/",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-clinical-impact-of-latent-drivers-from-double-mutations/385523.png","ImageObject",300,407,{"name":42,"@type":43},"CatatanPagi","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-29","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 are latent driver mutations in the study?","Question",{"text":63,"@type":64},"Latent driver mutations are rare mutations with low observable translational potential. Alone they appear marginal, but when paired in cis with other activating mutations, they can intensify oncogenic signaling.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How were potential latent drivers identified?",{"text":68,"@type":64},"The study performed comprehensive statistical analysis on pan-cancer mutation profiles of about 60,000 tumor sequences from TCGA and AACR-GENIE, identifying significantly co-occurring same-gene double mutations and cataloging their components as latent drivers.",{"name":70,"@type":61,"acceptedAnswer":71},"Do same-gene double mutations affect drug response?",{"text":72,"@type":64},"Yes. Evaluation using cell line data and patient-derived xenograft response data indicates that in certain genes, same-gene double mutations can increase oncogenic activity and yield better drug response, as shown for PIK3CA.","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},385523,1791398112,{"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},962090894170,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","ARTICLE   \n [https://doi.org/10.1038/s42003-023-04519-5](https://doi.org/10.1038/s42003-023-04519-5)  OPEN  \nPan-cancer clinical impact of latent drivers from double mutations  \nBengi Ruken Yavuz1, Chung-Jung Tsai  2, Ruth Nussinov2,3 & Nurcan Tuncbag  4,5,6✉  \nHere, we discover potential ‘ latent driver’ mutations in cancer genomes. Latent drivers have low frequencies and minor observable translational potential. As such, to date they have escaped identification. Their discovery is important, since when paired in cis, latent driver mutations can drive cancer. Our comprehensive statistical analysis of the pan-cancer mutation profiles of ~60,000 tumor sequences from the TCGA and AACR-GENIE cohortsidentifies significantly co-occurring potential latent drivers. We observe 155 same gene double mutations of which 140 individual components are cataloged as latent drivers. Evaluation of cell lines and patient-derived xenograft response data to drug treatment indicate that in certain genes double mutations may have a prominent role in increasing oncogenic activity, hence obtaining a better drug response, as in PIK3CA. Taken together, our comprehensive analyses indicate that same-gene double mutations are exceedingly rare phenomena but are a signature for some cancer types, e.g., breast, and lung cancers. The relative rarity of doublets can be explained by the likelihood of strong signals resulting in oncogeneinduced senescence, and by doublets consisting of non-identical single residue components populating the background mutational load, thus not identified.  \n1 Graduate School of Informatics, Department of Health Informatics, Middle East Technical University, Ankara 06800, Turkey. 2 Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA. 3 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. 4 Department of Chemical and Biological Engineering, College of Engineering, Koç University, Istanbul 34450, Turkey. 5 School of Medicine, Koç University, Istanbul 34450, Turkey. 6 Koc University Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul 34450, Turkey. ✉ email: [ntuncbag@ku.edu.tr](ntuncbag@ku.edu.tr)  \nCOMMUNICATIONS BIOLOGY | (2023)6:202 | [https://doi.org/10.1038/s42003-023-04519-5|www.nature.com/commsbio](https://doi.org/10.1038/s42003-023-04519-5|www.nature.com/commsbio) 1  \nC  \nancer is a disease of uncontrolled cell proliferation driven by molecular alterations. The impact of these alterations diffuses into the molecular interaction network and  \nchanges signaling pathways and transcriptional regulation in the cell. Not all alterations equally contribute to a growth advantage of cancer cells. Some mutations are drivers; others are passengers 1. Whereas it is generally believed that passenger mutations do not bestow proliferative effects on the disease phenotype, their properties, and possible roles are not fully understood2. Cancer genomics and evolution studies suggest that the accumulation of ‘slightly’ deleterious passenger mutations can slow cancer progression, and this could be exploited for therapeutic purposes3. Lately, another class of mutations was defined, dubbed “latent” or “mini-drivers”4–6. Even though not identified as drivers since the effect that latent drivers generate is marginal, when coupled with other activating mutations, latent mutations can additively intensify the signal. Their detection may help forecast cancer progression and improve personalized treatment strategies5. Curated driver genes and mutations have been deposited in multiple databases7–9 and used to develop computational approaches to predict driver genes and driver mutations 10–15. These methods, including frequency-based methods, subnetwork identification methods, and 3D mutation search methods, have been comprehensively compared 16–20. Oneof the","cbCaio36akNIKVFK","https://ap.wps.com/l/cbCaio36akNIKVFK","pdf",1955668,14,"English","# Introduction\n## Driver vs passenger and latent driver mutations\n## Double mutations in cis and therapeutic implications\n# Methods and analysis overview\n## Pan-cancer screening in TCGA and AACR-GENIE\n## Identification of co-occurring same-gene double mutations","[{\"question\":\"What are latent driver mutations in the study?\",\"answer\":\"Latent driver mutations are rare mutations with low observable translational potential. Alone they appear marginal, but when paired in cis with other activating mutations, they can intensify oncogenic signaling.\"},{\"question\":\"How were potential latent drivers identified?\",\"answer\":\"The study performed comprehensive statistical analysis on pan-cancer mutation profiles of about 60,000 tumor sequences from TCGA and AACR-GENIE, identifying significantly co-occurring same-gene double mutations and cataloging their components as latent drivers.\"},{\"question\":\"Do same-gene double mutations affect drug response?\",\"answer\":\"Yes. Evaluation using cell line data and patient-derived xenograft response data indicates that in certain genes, same-gene double mutations can increase oncogenic activity and yield better drug response, as shown for PIK3CA.\"}]","Pan-cancer clinical impact of latent drivers from double mutations | PDF",1790269778,35]