{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T17:26:25Z","timestamp":1789320385519,"version":"build-2803163510"},"reference-count":48,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T00:00:00Z","timestamp":1691020800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2018\/06269-5"],"award-info":[{"award-number":["2018\/06269-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2018\/17027-2"],"award-info":[{"award-number":["2018\/17027-2"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["FAPESP 2014\/50943-1"],"award-info":[{"award-number":["FAPESP 2014\/50943-1"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"CAPES","doi-asserted-by":"crossref","award":["88882.366031\/2019-01"],"award-info":[{"award-number":["88882.366031\/2019-01"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002322","name":"CAPES","doi-asserted-by":"crossref","award":["88887.136405\/2017-00"],"award-info":[{"award-number":["88887.136405\/2017-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002322","name":"CAPES","doi-asserted-by":"crossref","award":["88887.509818\/2020-00"],"award-info":[{"award-number":["88887.509818\/2020-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["426835\/2018-2"],"award-info":[{"award-number":["426835\/2018-2"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["465682\/2014-6"],"award-info":[{"award-number":["465682\/2014-6"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,7,11]]},"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic\/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>GPVs were detected in 21.5% (38\/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (<jats:italic>TP53<\/jats:italic>, <jats:italic>RB1<\/jats:italic>, <jats:italic>NF1<\/jats:italic>, <jats:italic>EXT1\/2<\/jats:italic>) but also in genes where that risk is still emerging\/limited (<jats:italic>ERCC2<\/jats:italic>, <jats:italic>TSC2<\/jats:italic> and <jats:italic>BRCA2<\/jats:italic>) or unknown (<jats:italic>PALB2<\/jats:italic>, <jats:italic>RAD50<\/jats:italic>, <jats:italic>FANCM<\/jats:italic> and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%\u00d76.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109269","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T13:21:19Z","timestamp":1691068879000},"page":"61-68","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes"],"prefix":"10.1136","volume":"61","author":[{"given":"Nathalia de Angelis de","family":"Carvalho","sequence":"first","affiliation":[{"name":"Clinical and Functional Genomics Group, ACCamargo Cancer Center, Sao Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6326-7795","authenticated-orcid":false,"given":"Karina Miranda","family":"Santiago","sequence":"additional","affiliation":[{"name":"Clinical and Functional Genomics Group, ACCamargo Cancer Center, Sao Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce Maria Lisboa","family":"Maia","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, ACCamargo Cancer Center, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe D\u2019Almeida","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, ACCamargo Cancer Center, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Nirvana","family":"Formiga","sequence":"additional","affiliation":[{"name":"Oncogenetics Department, ACCamargo Cancer Center, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diogo Cordeiro de Queiroz","family":"Soares","sequence":"additional","affiliation":[{"name":"Oncogenetics Department, ACCamargo Cancer Center, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Paix\u00e3o","sequence":"additional","affiliation":[{"name":"Oncogenetics Department, ACCamargo Cancer Center, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celso Abdon Lopes de","family":"Mello","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, ACCamargo Cancer Center, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia Maria Lima da","family":"Costa","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Department, ACCamargo Cancer Center, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Claudio Casali da","family":"Rocha","sequence":"additional","affiliation":[{"name":"Oncogenetics Department, ACCamargo Cancer Center, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9434-6288","authenticated-orcid":false,"given":"Barbara","family":"Rivera","sequence":"additional","affiliation":[{"name":"Molecular Mechanisms and Experimental Therapy in Oncology Program, IDIBELL, Barcelona, Spain"},{"name":"Gerald Bronfman Department of Oncology, McGill University, Montreal, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirce Maria","family":"Carraro","sequence":"additional","affiliation":[{"name":"Clinical and Functional Genomics Group, ACCamargo Cancer Center, Sao Paulo, S\u00e3o Paulo, Brazil"},{"name":"National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8659-5329","authenticated-orcid":false,"given":"Giovana Tardin","family":"Torrezan","sequence":"additional","affiliation":[{"name":"Clinical and Functional Genomics Group, ACCamargo Cancer Center, Sao Paulo, S\u00e3o Paulo, Brazil"},{"name":"National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,8,3]]},"reference":[{"key":"2025100511255182000_61.1.61.1","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/jso.23809","article-title":"Etiologic, environmental and inherited risk factors in sarcomas","volume":"111","author":"Thomas","year":"2015","journal-title":"J Surg Oncol"},{"key":"2025100511255182000_61.1.61.2","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2016-0079"},{"key":"2025100511255182000_61.1.61.3","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1097\/PAP.0000000000000284","article-title":"The 2020 WHO classification of tumors of soft tissue: selected changes and new entities","volume":"28","author":"Choi","year":"2021","journal-title":"Adv Anat Pathol"},{"key":"2025100511255182000_61.1.61.4","doi-asserted-by":"publisher","DOI":"10.1088\/0952-4746\/29\/2A\/S05"},{"key":"2025100511255182000_61.1.61.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30147-4"},{"key":"2025100511255182000_61.1.61.6","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.21040"},{"key":"2025100511255182000_61.1.61.7","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djk002"},{"key":"2025100511255182000_61.1.61.8","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1007\/s00247-008-1015-6","article-title":"Radiation-sensitive genetically susceptible pediatric sub-populations","volume":"39 Suppl 1","author":"Kleinerman","year":"2009","journal-title":"Pediatr Radiol"},{"key":"2025100511255182000_61.1.61.9","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/S1470-2045(16)30292-3","article-title":"Are sarcomas hereditary?","volume":"17","author":"Benjamin","year":"2016","journal-title":"Lancet Oncol"},{"key":"2025100511255182000_61.1.61.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.039"},{"key":"2025100511255182000_61.1.61.11","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1097\/PAP.0000000000000190","article-title":"Tumor syndromes predisposing to osteosarcoma","volume":"25","author":"Hameed","year":"2018","journal-title":"Adv Anat Pathol"},{"key":"2025100511255182000_61.1.61.12","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.21037\/tau-20-76","article-title":"Germline predisposition to genitourinary rhabdomyosarcoma","volume":"9","author":"Schneider","year":"2020","journal-title":"Transl Androl Urol"},{"key":"2025100511255182000_61.1.61.13","article-title":"Pathogenic germline variants in cancer susceptibility genes in children and young adults with rhabdomyosarcoma","volume":"5","author":"Kim","year":"2021","journal-title":"JCO Precis Oncol"},{"key":"2025100511255182000_61.1.61.14","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1001\/jamaoncol.2020.0197","article-title":"Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma","volume":"6","author":"Mirabello","year":"2020","journal-title":"JAMA Oncol"},{"key":"2025100511255182000_61.1.61.15","doi-asserted-by":"publisher","DOI":"10.1038\/nature12981"},{"key":"2025100511255182000_61.1.61.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0528-2"},{"key":"2025100511255182000_61.1.61.17","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0093455","article-title":"A two-dimensional pooling strategy for rare variant detection on next-generation sequencing platforms","volume":"9","author":"Zuzarte","year":"2014","journal-title":"PLoS One"},{"key":"2025100511255182000_61.1.61.18","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025100511255182000_61.1.61.19","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-8-54","article-title":"Mutational spectrum of the APC and MUTYH genes and genotype\u2013phenotype correlations in Brazilian FAP, AFAP, and MAP patients","volume":"8","author":"Torrezan","year":"2013","journal-title":"Orphanet J Rare Dis"},{"key":"2025100511255182000_61.1.61.20","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1016\/j.cllc.2019.11.012","article-title":"High prevalence of EGFR mutations in lung adenocarcinomas from Brazilian patients harboring the Tp53 P.R337H variant","volume":"21","author":"Barbosa","year":"2020","journal-title":"Clin Lung Cancer"},{"key":"2025100511255182000_61.1.61.21","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.aba3231","article-title":"Xaf1 as a modifier of P53 function and cancer susceptibility","volume":"6","author":"Pinto","year":"2020","journal-title":"Sci Adv"},{"key":"2025100511255182000_61.1.61.22","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0337"},{"key":"2025100511255182000_61.1.61.23","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2020.571330","article-title":"Using Co-segregation and loss of heterozygosity analysis to define the pathogenicity of unclassified variants in hereditary breast cancer patients","volume":"10","author":"Grasel","year":"2020","journal-title":"Front Oncol"},{"key":"2025100511255182000_61.1.61.24","doi-asserted-by":"crossref","DOI":"10.1038\/s41523-021-00361-2","article-title":"Value of the loss of heterozygosity to BRCA1 variant classification","volume":"8","author":"Santana Dos Santos","year":"2022","journal-title":"NPJ Breast Cancer"},{"key":"2025100511255182000_61.1.61.25","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.3390\/cancers12071848","article-title":"Clinical and molecular assessment of patients with Lynch syndrome and Sarcomas underpinning the association with MSH2 Germline pathogenic variants","volume":"12","author":"de Angelis de Carvalho","year":"2020","journal-title":"Cancers"},{"key":"2025100511255182000_61.1.61.26","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-29575-z","article-title":"Author correction: whole-genome sequencing of 1,171 elderly admixed individuals from Brazil","volume":"13","author":"Naslavsky","year":"2022","journal-title":"Nat Commun"},{"key":"2025100511255182000_61.1.61.27","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1016\/j.gim.2022.04.017","article-title":"The gene curation coalition: a global effort to harmonize gene-disease evidence resources","volume":"24","author":"DiStefano","year":"2022","journal-title":"Genet Med"},{"key":"2025100511255182000_61.1.61.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.04.007"},{"key":"2025100511255182000_61.1.61.29","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-10333-x","article-title":"Germline mutations in cancer predisposition genes are frequent in sporadic sarcomas","volume":"7","author":"Chan","year":"2017","journal-title":"Sci Rep"},{"key":"2025100511255182000_61.1.61.30","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.134"},{"key":"2025100511255182000_61.1.61.31","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.wneu.2017.10.064","article-title":"Malignant peripheral nerve sheath tumor in a patient with BAP1 tumor predisposition syndrome","volume":"109","author":"Kaszuba","year":"2018","journal-title":"World Neurosurg"},{"key":"2025100511255182000_61.1.61.32","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0227260","article-title":"The Brazilian TP53 Mutation (R337H) and sarcomas","volume":"15","author":"Volc","year":"2020","journal-title":"PLoS One"},{"key":"2025100511255182000_61.1.61.33","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.26390"},{"key":"2025100511255182000_61.1.61.34","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.3711"},{"key":"2025100511255182000_61.1.61.35","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a026195","article-title":"The inherited P53 mutation in the Brazilian population","volume":"6","author":"Achatz","year":"2016","journal-title":"Cold Spring Harb Perspect Med"},{"key":"2025100511255182000_61.1.61.36","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1001\/jamaoncol.2016.6389","article-title":"Frequency of thyroid carcinoma in Brazilian TP53P. R337H carriers with Li Fraumeni syndrome","volume":"3","author":"Formiga","year":"2017","journal-title":"JAMA Oncol"},{"key":"2025100511255182000_61.1.61.37","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1093\/carcin\/bgx089","article-title":"Spectrum of germline mutations in Smokers and non-Smokers in Brazilian non-small-cell lung cancer (NSCLC) patients","volume":"38","author":"Couto","year":"2017","journal-title":"Carcinogenesis"},{"key":"2025100511255182000_61.1.61.38","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1001\/jamaoncol.2015.4771","article-title":"Multilocus inherited neoplasia alleles syndrome: a case series and review","volume":"2","author":"Whitworth","year":"2016","journal-title":"JAMA Oncol"},{"key":"2025100511255182000_61.1.61.39","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41431-021-01013-6","article-title":"Multilocus inherited neoplasia allele syndrome (MINAS): an update","volume":"30","author":"McGuigan","year":"2022","journal-title":"Eur J Hum Genet"},{"key":"2025100511255182000_61.1.61.40","doi-asserted-by":"publisher","DOI":"10.1038\/nature10539"},{"key":"2025100511255182000_61.1.61.41","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ejcb.2013.10.002","article-title":"A germline oncogenic MITF mutation and tumor susceptibility","volume":"93","author":"Paillerets","year":"2014","journal-title":"Eur J Cell Biol"},{"key":"2025100511255182000_61.1.61.42","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-74237-z","article-title":"Cancer risks associated with the Germline MITF(E318K) variant","volume":"10","author":"Guhan","year":"2020","journal-title":"Sci Rep"},{"key":"2025100511255182000_61.1.61.43","doi-asserted-by":"crossref","DOI":"10.1186\/s13053-021-00189-8","article-title":"Expanding the phenotype of E318K (C.952G\u2009>\u2009A) MITF germline mutation carriers: case series and review of the literature","volume":"19","author":"Oliveira","year":"2021","journal-title":"Hered Cancer Clin Pract"},{"key":"2025100511255182000_61.1.61.44","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.100296"},{"key":"2025100511255182000_61.1.61.45","doi-asserted-by":"publisher","DOI":"10.1002\/path.4510"},{"key":"2025100511255182000_61.1.61.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.07.006"},{"key":"2025100511255182000_61.1.61.47","unstructured":"National Comprehensive Cancer Network . Bone cancer (version 1.2023). Available: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/bone.pdf [Accessed 25 Sep 2022]."},{"key":"2025100511255182000_61.1.61.48","unstructured":"National Comprehensive Cancer Network . Soft tissue sarcoma (version 2.2022). Available: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/sarcoma.pdf [Accessed 25 Sep 2022]."}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2023-109269","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T18:26:00Z","timestamp":1759688760000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2023-109269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,3]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12,21]]},"published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1136\/jmg-2023-109269"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2023-109269","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,3]]}}}