[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-375709-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-375709-en":131},{"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","chek2-germline-variants-identified-in-familial-nonmedullary-thyroid-cancer-impaired-protein-structure-and-function","CHEK2 germline variants identified in familial nonmedullary thyroid cancer - impaired protein structure and function","","Genetic causes of familial nonmedullary thyroid cancers (FNMTC) remain largely unclear, limiting diagnosis and clinical management. Two FNMTC families were studied using next-generation sequencing of 94 hereditary cancer predisposition genes, identifying two germline CHEK2 missense variants that segregated with thyroid cancer. Biophysical methods, molecular dynamics simulations, and immunohistochemistry showed compromised structural stability, impaired kinase activity, and amyloid-like aggregation in vitro. Findings support complementary in silico and biophysical approaches for clinical translation of CHEK2 variant impact.",{"@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/chek2-germline-variants-identified-in-familial-nonmedullary-thyroid-cancer-impaired-protein-structure-and-function/375709/",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/chek2-germline-variants-identified-in-familial-nonmedullary-thyroid-cancer-impaired-protein-structure-and-function/375709.png","ImageObject",300,407,{"name":42,"@type":43},"Riley","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",13,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What genetic variants were identified in the two studied FNMTC families?","Question",{"text":63,"@type":64},"Two germline CHEK2 missense variants were found: c.962A>C (p.E321A) and c.470T>C (p.I157T), and each variant segregated with thyroid cancer within its family.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How were the CHEK2 protein variants characterized for functional impact?",{"text":68,"@type":64},"The study used biophysical methods, molecular dynamics simulations, and immunohistochemistry to compare wild-type and variant CHK2 proteins.",{"name":70,"@type":61,"acceptedAnswer":71},"What functional and structural effects did the CHEK2 variants show?",{"text":72,"@type":64},"Compared with the wild-type protein, the variants exhibited compromised structural/conformational stability, impaired kinase activity, and a higher propensity for amyloid-like fibril aggregation in vitro.","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},375709,1790274259,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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familial nonmedullary thyroid cancer lead to impaired protein structure and function  \nReceived for publication, July 13, 2023, and in revised form, February 9, 2024 Published, Papers in Press, February 16, 2024, [https://doi.org/10.1016/j.jbc.2024.105767](https://doi.org/10.1016/j.jbc.2024.105767)  \nCarolina Pires 1,2, Inês J. Marques 1,2, Mariana Valério3, Ana Saramago 1, Paulo E. Santo4, Sandra Santos4, Margarida Silva4, Margarida M. Moura 1, João Matos5, Teresa Pereira5, Rafael Cabrera5, Diana Lousa3, Valeriano Leite 1,6, Tiago M. Bandeiras4, João B. Vicente3, and Branca M. Cavaco 1, *  \nFrom the 1Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; 2NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal; 3Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal; 4Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal; 5Serviço de Anatomia Patológica, and 6Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal  \nReviewed by members of the JBC Editorial Board. Edited by Eric Fearon  \nApproximately 5 to 15% of nonmedullary thyroid cancers (NMTC) present in a familial form (familial nonmedullary thyroid cancers [FNMTC]). The genetic basis of FNMTC remains largely unknown, representing a limitation for diagnostic and clinical management. Recently, germline mutations in DNA repair-related genes have been described in cases with thyroid cancer (TC), suggesting a role in FNMTC etiology. Here, two FNMTC families were studied, each with two members affected with TC. Ninety-four hereditary cancer predisposition genes were analyzed through next-generation sequencing, revealing two germline CHEK2 missense variants (c.962A > C, p.E321A and c.470T > C, p.I157T), which segregated with TC in each FNMTC family. p.E321A, located in the CHK2 protein kinase domain, is a rare variant, previously unreported in the literature. Conversely, p.I157T, located in CHK2 forkhead-associated domain, has been extensively described, having conflicting interpretations of pathogenicity. CHK2 proteins (WT and variants) were characterized using biophysical methods, molecular dynamics simulations, and immunohistochemistry. Overall, biophysical characterization ofthese CHK2variants showed that they have compromised structural and conformational stability and impaired kinase activity, compared to the WT protein. CHK2 appears to aggregate into amyloid-like fibrils in vitro, which opens future perspectives toward positioning CHK2 in cancer pathophysiology. CHK2 variants exhibited higher propensity for this conformational change, also displaying higher expression in thyroid tumors. The present findings support the utility of complementary biophysical and in silico approaches toward understanding the impact of genetic variants in protein structure and function, improving the current knowledge on CHEK2 variants’ role in FNMTC genetic basis, with prospective clinical translation.  \n* For correspondence: Branca M. Cavaco, [bcavaco@ipolisboa.min-saude.pt](bcavaco@ipolisboa.min-saude.pt).  \nThyroid cancer (TC) is the most common endocrine malignancy, accounting for 􀀁 3% of all cancer diagnoses worldwide (1). It continues to be the most rapidly increasing cancer type, with a male/female ratio of 1:3 (2). Most thyroid tumors (approximately 95%) are derived from the thyroid follicular cells and are designated as nonmedullary thyroid cancers (NMTC) (3). Although the majority of these tumors are sporadic, 5 to 15% of all follicular cell-derived thyroid tumors are familial, being designated as familial nonmedullary thyroid cancers (FNMTC). In FNMTC families, patients frequently present TC together with benign lesions [e.g., thyroid follicular nodular disease (FND) and follicular thyroid adenomas], wi","cbCaipVVraf5sHEk","https://ap.wps.com/l/cbCaipVVraf5sHEk","pdf",3457110,15,"English","# Background\n## Familial nonmedullary thyroid cancer and genetic uncertainty\n# Study design\n## Patient families and gene panel sequencing\n## Identified CHEK2 variants\n# Functional characterization\n## Biophysical assessment and molecular dynamics\n## Immunohistochemistry and conformational changes\n# Implications\n## Relevance to cancer pathophysiology and clinical translation","[{\"question\":\"What genetic variants were identified in the two studied FNMTC families?\",\"answer\":\"Two germline CHEK2 missense variants were found: c.962A\\u003eC (p.E321A) and c.470T\\u003eC (p.I157T), and each variant segregated with thyroid cancer within its family.\"},{\"question\":\"How were the CHEK2 protein variants characterized for functional impact?\",\"answer\":\"The study used biophysical methods, molecular dynamics simulations, and immunohistochemistry to compare wild-type and variant CHK2 proteins.\"},{\"question\":\"What functional and structural effects did the CHEK2 variants show?\",\"answer\":\"Compared with the wild-type protein, the variants exhibited compromised structural/conformational stability, impaired kinase activity, and a higher propensity for amyloid-like fibril aggregation in vitro.\"}]","CHEK2 germline variants identified in familial nonmedullary thyroid cancer - impaired protein structure and function | PDF",1790215842,38]