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This study catalogs mutations across 500 kinase genes in over 65,000 individuals from global HGDP and ExAC datasets, then evaluates potentially deleterious effects using SIFT, PolyPhen2, and CADD. Results identify 35 deleterious non-synonymous variants in ExAC and 5 in HGDP, with enrichment in NTRK1 and FGFR3. Expression and drug-target analyses suggest personalized therapeutic leads.",{"@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/predisposing-deleterious-variants-in-the-cancer-associated-human-kinases-in-the-global-populations-research-article/327433/",{"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/predisposing-deleterious-variants-in-the-cancer-associated-human-kinases-in-the-global-populations-research-article/327433.png","ImageObject",300,407,{"name":92,"@type":93},"Emma Wilson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main aim of this study?","Question",{"text":112,"@type":113},"To catalog potentially deleterious genetic variants in cancer-associated human kinases across global populations and assess their likely impact and relevance to cancer mechanisms.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which in silico tools were used to evaluate deleterious mutations?",{"text":117,"@type":113},"SIFT, PolyPhen2, and CADD were used to assess the potentially deleterious impact of variants.",{"name":119,"@type":110,"acceptedAnswer":120},"Which kinase genes were most significantly enriched in the analysis?",{"text":121,"@type":113},"The gene set enrichment analysis highlighted NTRK1 and FGFR3 as the most significantly enriched among the kinases.","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},327433,1790640747,{"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":24,"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,"preview_page_count":4},3848291630094,"https://eur-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","PLOS ONE  \nOPEN ACCESS  \nCitation: Khan SA, Anwar M, Gohar A, Roosan MR, Hoessli DC, Khatoon A, et al. (2024) Predisposing deleterious variants in the cancer-associated human kinases in the global populations. PLoSONE 19(4): e0298747 . [https://doi.org/10.1371/](https://doi.org/10.1371/)[ ](https://doi.org/10.1371/)[journal.pone.0298747](journal.pone.0298747)  \nEditor: Syed M. Faisal, University of Michigan Medical School, UNITED STATES  \nReceived: October 4, 2023  \nAccepted: January 29, 2024  \nPublished: April 18, 2024  \nCopyright: © 2024 Khan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  \nData Availability Statement: All relevant data are within the manuscript and its Supporting Information files.  \nFunding: The author(s) received no specific funding for this work.  \nCompeting interests: The authors declare that there are no any competing interests.  \nRESEARCH ARTICLE  \nPredisposing deleterious variants in the cancer-associated human kinases in the global populations  \nSalman Ahmed Khan1,2 *, Misbah Anwar3, Atia Gohar4, Moom R. Roosan5, Daniel  \nC. Hoessli3, Ambrina Khatoon6, Muhammad Shakeel3 *  \n1 Department of Molecular Medicine (DMM), Dow College of Biotechnology (DCoB), Dow University of Health Sciences (DUHS), Karachi, Pakistan, 2 DOW-DOGANA Advanced Molecular Genetics and Genomics Disease Research and Treatment Center (AMGGDRTC), Dow University of Health Sciences (DUHS), Karachi, Pakistan, 3 Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan, 4 H. E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan, 5 Department of Pharmacy Practice, Chapman University School of Pharmacy Harry and Diane Rinker Health Science Campus, Irvine, CA, United States of America, 6 Department of Molecular Medicine, Ziauddin University, Karachi, Pakistan  \n* [dr.salman@duhs.edu.pk](dr.salman@duhs.edu.pk), [salman_ahmedkhan@hotmail.com](salman_ahmedkhan@hotmail.com) (SAK); mshakeel_21 [1@yahoo.com](1@yahoo.com) (MS)  \nAbstract  \nHuman kinases play essential and diverse roles in the cellular activities of maintaining homeostasis and growth. Genetic mutations in the genes encoding the kinases (or phosphotransferases) have been linked with various types of cancers. In this study, we cataloged mutations in 500 kinases genes in >65,000 individuals of global populations from the Human Genetic Diversity Project (HGDP) and ExAC databases, and assessed their potentially deleterious impact by using the in silico tools SIFT, Polyphen2, and CADD. The analysis highlighted 35 deleterious non-synonymous SNVs in the ExAC and 5 SNVs in the HGDP project. Notably, a higher number of deleterious mutations was observed in the Non-Finnish Europeans (26 SNVs), followed by the Africans (14 SNVs), East Asians (13 SNVs), and South Asians (12 SNVs) . The gene set enrichment analysis highlighted NTRK1 and FGFR3 being most significantly enriched among the kinases. The gene expression analysis revealed over-expression of NTRK1 in liver cancer, whereas, FGFR3 was found overexpressed in lung, breast, and liver cancers compared to their expression in the respective normal tissues. Also, 13 potential drugs were identified that target the NTRK1 protein, whereas 6 potential drugs for the FGFR3 target were identified. Taken together, the study provides a framework for exploring the predisposing germline mutations in kinases to suggest the underlying pathogenic mechanisms in cancers. The potential drugs are also suggested for personalized cancer management.  \n1. Introduction  \nAmong all the biological molecules, proteins are the key comp","cbCaie7b38qbozYN","https://ap.wps.com/l/cbCaie7b38qbozYN","pdf",1253972,16,"English","# Abstract\n# Introduction\n## Protein kinases and phosphorylation in cellular processes\n## Kinase families and links to disease and cancer therapy","[{\"question\":\"What is the main aim of this study?\",\"answer\":\"To catalog potentially deleterious genetic variants in cancer-associated human kinases across global populations and assess their likely impact and relevance to cancer mechanisms.\"},{\"question\":\"Which in silico tools were used to evaluate deleterious mutations?\",\"answer\":\"SIFT, PolyPhen2, and CADD were used to assess the potentially deleterious impact of variants.\"},{\"question\":\"Which kinase genes were most significantly enriched in the analysis?\",\"answer\":\"The gene set enrichment analysis highlighted NTRK1 and FGFR3 as the most significantly enriched among the kinases.\"}]","Predisposing deleterious variants in the cancer-associated human kinases in the global populations - research article | PDF",1789977198]