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Using ultra-deep duplex sequencing (mean ~15,000×), the study analyzes somatic mutation and selection in an LFS family carrying TP53 p. R181H and in non-carrier controls. Blood profiling links the germline variant to higher mutation burden and altered selection on somatic TP53. The work also maps parallel TP53 hotspot emergence across tissues and shows phase details tied to the non-variant chromosome.",{"@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/ultra-deep-duplex-sequencing-reveals-unique-features-of-somatic-evolution-in-the-normal-tissues-of-a-family-with-li-fraumeni-syndrome/344712/",{"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/ultra-deep-duplex-sequencing-reveals-unique-features-of-somatic-evolution-in-the-normal-tissues-of-a-family-with-li-fraumeni-syndrome/344712.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main scientific question addressed by this study?","Question",{"text":112,"@type":113},"How Li-Fraumeni Syndrome, caused by germline TP53 pathogenic variants, shapes clonal evolution and somatic mutation/selection in healthy tissues before cancer develops.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which sequencing approach and sample types were used?",{"text":117,"@type":113},"Ultra-deep duplex sequencing (mean ~15,000×) was used, including blood samples and extensive multi-tissue sampling from an autopsy in an individual with LFS.",{"name":119,"@type":110,"acceptedAnswer":120},"What key findings were observed regarding TP53 mutations across tissues?",{"text":121,"@type":113},"The study reports excess somatic mutations in specific tissues and highly parallel emergence of TP53 mutations at the p. R248 hotspot across many tissue samples, with phase often arising on the chromosomal copy lacking the p. R181H variant.","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},344712,1790183942,{"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":14,"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},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","bioRxiv preprint doi: [https://doi.org/10.64898/2026.01.12.699071](https://doi.org/10.64898/2026.01.12.699071); this version posted January 13, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY 4.0 International license.  \nUltra-deep duplex sequencing reveals unique features of somatic evolution in the normal tissues of a family with Li-Fraumeni syndrome  \nHunter L. Colegrove1 , Marianne E Dubard-Gault2,3,4 , Henry Marshall5 , Brendan F. Kohrn6 , Thomas H. Smith7 , Zachary K. Norgaard7 , Fang Yin Lo7 , Elizabeth K. Schmidt7 , Jacob E. Higgins7 , Charles C. Valentine III7 , Desiree A. Marshall6 , John I. Clark8 , Eric Q. Konnick6 , Jesse J. Salk7,9 , Marshall S. Horwitz6 , Raheleh Rahbari5 , Alison F. Feder1,10,11,12*, Rosa Ana Risques6,12*  \n1 Department of Genome Sciences, University of Washington; Seattle, WA, USA.  \n2 Fred Hutchinson Cancer Center; Seattle, WA, USA.  \n3 Department of Medicine, Division of Medical Genetics, University of Washington; Seattle, WA, USA.  \n4 Providence Swedish Cancer Institute; Seattle, WA, USA.  \n5 Wellcome Sanger Institute; Hinxton, UK.  \n6 Department of Laboratory Medicine and Pathology, University of Washington; Seattle, WA, USA.  \n7 TwinStrand Biosciences; Seattle, WA, USA.  \n8 Department of Neurobiology & Biophysics, University of Washington; Seattle, WA, USA.  \n9 Department of Medicine, Division of Hematology and Oncology, University of Washington; Seattle, WA, USA.  \n10 Herbold Computational Biology Program, Fred Hutch Cancer Center; Seattle, WA, USA.  \n11 Howard Hughes Medical Institute; Seattle, WA, USA.  \n12 These authors jointly supervised this work.  \n*Corresponding authors:  \nAlison Feder, PhD Email: [affeder@uw.edu](affeder@uw.edu)[ ](affeder@uw.edu)Rosa Ana Risques, PhD Email: [rrisques@uw.edu](rrisques@uw.edu)  \nShort title: Somatic evolution in Li-Fraumeni Syndrome  \nKeywords: TP53 mutations, duplex sequencing, selection, clonal expansion, somatic mutations, mutational signatures  \nbioRxiv preprint doi: [https://doi.org/10.64898/2026.01.12.699071](https://doi.org/10.64898/2026.01.12.699071); this version posted January 13, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY 4.0 International license.  \nABSTRACT  \nLi-Fraumeni Syndrome (LFS) is caused by germline pathogenic variants in TP53 which predispose carriers to early onset cancer across multiple tissues. While genomically profiling those cancers has revealed factors contributing to their formation, little is understood about how LFS impacts clonal evolution in healthy tissues preceding cancer. Here, we use ultra-deep duplex sequencing (mean ~15,000× depth) to investigate somatic mutation and selection in a family carrying the germline TP53 p. R181H pathogenic variant and a cohort of non-carrier controls. In blood samples, the germline variant was associated with more mutations in a panel designed to capture genomewide mutagenesis, and with reduced positive selection on somatic TP53 mutations, despite confounding by chemotherapy treatment in one individual. DNMT3A and TET2 mutations were positively selected and GATA2 mutations were negatively selected across the cohort, independent of thep. R181H status. Extensive multi-tissue sampling of 22 non-cancerous and 6 cancerous samples was also performed at autopsy in one individual with LFS who succumbed to esophageal cancer. Cross-tissue analysis revealed excess mutations in sun-exposed skin, esophagus and chronically-inflamed stomach tissue, and highly parallel emergence of mutations in the p. R248 hotspot of TP53 across most (18/28) tissue samples. Most somatic TP53 mutations in LFS that could be assessed for phase arose on the chromosomal copy lacki","cbCaiaMKL8h75BZF","https://ap.wps.com/l/cbCaiaMKL8h75BZF","pdf",2915645,22,"English","# Abstract\n# Introduction","[{\"question\":\"What is the main scientific question addressed by this study?\",\"answer\":\"How Li-Fraumeni Syndrome, caused by germline TP53 pathogenic variants, shapes clonal evolution and somatic mutation/selection in healthy tissues before cancer develops.\"},{\"question\":\"Which sequencing approach and sample types were used?\",\"answer\":\"Ultra-deep duplex sequencing (mean ~15,000×) was used, including blood samples and extensive multi-tissue sampling from an autopsy in an individual with LFS.\"},{\"question\":\"What key findings were observed regarding TP53 mutations across tissues?\",\"answer\":\"The study reports excess somatic mutations in specific tissues and highly parallel emergence of TP53 mutations at the p. R248 hotspot across many tissue samples, with phase often arising on the chromosomal copy lacking the p. R181H variant.\"}]","Ultra-deep duplex sequencing reveals unique features of somatic evolution in the normal tissues of a family with Li-Fraumeni syndrome | PDF",1790055028,55]