[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-331305-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-331305-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","germline-variant-affecting-p53-isoforms-predisposes-to-familial-cancer","Germline variant affecting p53β isoforms predisposes to familial cancer","","Germline and somatic TP53 variants shape tumorigenesis, yet changes restricted to alternatively spliced p53 isoforms are less considered in Li-Fraumeni syndrome diagnosis. Whole-exome analysis of four families with autosomal dominant cancer risk identifies a heterozygous stop-lost variant in p53β (p.*342Serext*17). The variant extends p53β by 17 amino acids, enhancing oligomerization with canonical p53α and disrupting transcriptional target regulation. Findings show p53β mutants can modulate p53 signaling and influence susceptibility across distinct cancer types, supporting comprehensive TP53 investigation.",{"@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/research-report/","Research & 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where does it affect TP53?","Question",{"text":63,"@type":64},"A heterozygous stop-lost variant affecting the alternatively spliced p53β isoforms was identified in cryptic exon 9β of the TP53 gene (p.*342Serext*17).","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does the stop-lost p53β variant change p53β function?",{"text":68,"@type":64},"It produces a 17-amino-acid extension of p53β, increasing oligomerization with canonical p53α and dysregulating the expression of p53 transcriptional targets.",{"name":70,"@type":61,"acceptedAnswer":71},"Why is the study important for diagnosing Li-Fraumeni syndrome?",{"text":72,"@type":64},"It highlights that variants limited to p53 isoforms (rather than full-length TP53 coding exons) can contribute to cancer predisposition, supporting comprehensive investigation of the entire TP53 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\nGermline variant affecting p53β isoforms predisposes to familial cancer  \nReceived: 8 May 2020  \n\n| Accepted: 6 September 2024 |\n| --- |\n| |\n| Check for updates |\n\nStephanie A. Schubert 1, Dina Ruano1, Sebastien M. Joruiz 2, Jordy Stroosma1, Nikolina Glavak 2,3, Anna Montali 2, Lia M. Pinto 2, Mar Rodríguez-Girondo4,  \nDaniela Q. C. M. Barge-Schaapveld 5, Maartje Nielsen 5, Bernadette P. M. van Nesselrooij6, Arjen R. Mensenkamp 7, Monique E. van Leerdam8, Thomas H. Sharp 9,10, Hans Morreau 1, Jean-Christophe Bourdon 2 , Noel F. C. C. de Miranda 1  & Tom van Wezel 1,11   \nGermline and somatic TP53 variants play a crucial role during tumorigenesis. However, genetic variations that solely affect the alternatively spliced p53 isoforms, p53β and p53γ, are not fully considered in the molecular diagnosis of Li-Fraumeni syndrome and cancer. In our search for additional cancer predisposing variants, we identify a heterozygous stop-lost variant affecting thep53β isoforms (p.*342Serext*17) in four families suspected of an autosomal dominant cancer syndrome with colorectal, breast and papillary thyroid cancers. The stop-lost variant leads to the 17 amino-acid extension of the p53β isoforms, which increases oligomerization to canonical p53α and dysregulates the expression of p53’s transcriptional targets. Our study reveals the capacity of p53β mutants to influence p53 signalling and contribute to the susceptibility of different cancer types. These findings underscore the significance of p53 isoforms and the necessity ofcomprehensive investigation into the entire TP53 gene in understanding cancer predisposition.  \nA substantial proportion of cancer patients have a familial history of disease, although the extent of this phenomenon is dependent on the type of cancer1. For instance, disease clustering within families can be observed in 20–30% of colorectal cancer patients, 15–20% of breast cancer patients, and ~5% of papillary thyroid cancer patients2–5. However, the genetic cause of familial cancer predisposition is only known in approximately half the familial colorectal and breast cancer cases and remains largely elusive formost of the familial papillary thyroid cancers. In contrast to most inherited cancer syndromes, that predominantly affect specific  \norgans, Li-Fraumeni syndrome (OMIM\\#151623) predisposes to a variety of early-onset cancers, including breast cancer, bone and soft tissue sarcomas, brain cancer, and to a lesser extent, colorectal cancer and thyroid cancer (2015 revised Chompret criteria)6. Pathogenic germline variants in the TP53 gene are responsible formost cases of Li-Fraumeni syndrome, however different pathogenic variants confer varying cancer risks and are associated with different types of tumors7–11.  \nThe TP53 gene encodes at least 12 different p53 protein isoforms. This results from the combination of four translation initiation sites  \n1Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 2School of Medicine, University of Dundee, Dundee, UK. 3Croatian Institute of Transfusion Medicine, Zagreb, Croatia. 4Department of Biomedical Data Sciences, Section of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands. 5Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 6Department of Clinical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 7Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 8Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. 9Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. 10School of Biochemistry, University of Bristol, Bristol, UK. 11Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. [e-mail:](e-mail: j.bourdon@dund","cbCailMVsZwGbJ72","https://ap.wps.com/l/cbCailMVsZwGbJ72","pdf",1486698,15,"English","# Background\n## Familial cancer clustering and Li-Fraumeni syndrome\n# TP53 isoforms and diagnostic gap\n## Cryptic exons and current sequencing practice\n# Study approach\n## Whole-exome sequencing in suspected hereditary cases\n# Results\n## Identification of the cancer susceptibility variant\n## Functional impact on p53 signaling","[{\"question\":\"What variant was identified and where does it affect TP53?\",\"answer\":\"A heterozygous stop-lost variant affecting the alternatively spliced p53β isoforms was identified in cryptic exon 9β of the TP53 gene (p.*342Serext*17).\"},{\"question\":\"How does the stop-lost p53β variant change p53β function?\",\"answer\":\"It produces a 17-amino-acid extension of p53β, increasing oligomerization with canonical p53α and dysregulating the expression of p53 transcriptional targets.\"},{\"question\":\"Why is the study important for diagnosing Li-Fraumeni syndrome?\",\"answer\":\"It highlights that variants limited to p53 isoforms (rather than full-length TP53 coding exons) can contribute to cancer predisposition, supporting comprehensive investigation of the entire TP53 gene.\"}]","Germline variant affecting p53β isoforms predisposes to familial cancer | PDF",1789992598,38]