{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:25:33Z","timestamp":1790807133794,"version":"4.1.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T00:00:00Z","timestamp":1714694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n TP53 alterations are common in certain pediatric cancers, making identification of putative germline variants through tumor genomic profiling crucial for disease management.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We analyzed TP53 alterations in 3123 tumors from 2788 pediatric patients sequenced using tumor-only or tumor-normal paired panels. Germline confirmatory testing was performed when indicated. Somatic and germline variants were classified based on published guidelines.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n In 248 tumors from 222 patients, 284 tier 1\/2 TP53 sequence and small copy number variants were detected. Following germline classification, 86.6% of 142 unique variants were pathogenic or likely pathogenic. Confirmatory testing on 118 patients revealed germline TP53 variants in 28 of them (23 pathogenic or likely pathogenic and 5 of uncertain significance), suggesting a minimum Li-Fraumeni syndrome incidence of 0.8% (23\/2788) in this cohort, 10.4% (23\/222) in patients with TP53 variant\u2013carrying tumors, and 19.5% (23\/118) with available normal samples. About 25% (7\/28) of patients with germline TP53 variants did not meet Li-Fraumeni syndrome diagnostic or testing criteria, while 20.9% (28\/134) with confirmed or inferred somatic origins did. TP53 biallelic inactivation occurred in 75% of germline carrier tumors and was also prevalent in other groups, causing an elevated tumor-observed variant allelic fraction. Somatic evidence, however, including low variant allele fraction correctly identified only 27.8% (25\/90) of patients with confirmed somatic TP53 variants.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n The high incidence and variable phenotype of Li-Fraumeni syndrome in this cohort highlights the importance of assessing germline status of TP53 variants identified in all pediatric tumors. Without clear somatic evidence, distinguishing somatic from germline origins is challenging. Classifying germline and somatic variants should follow appropriate guidelines.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/jnci\/djae102","type":"journal-article","created":{"date-parts":[[2024,5,4]],"date-time":"2024-05-04T03:14:05Z","timestamp":1714792445000},"page":"1356-1365","source":"Crossref","is-referenced-by-count":7,"title":["Identification of TP53<\/i> germline variants in pediatric patients undergoing tumor testing: strategy and prevalence"],"prefix":"10.1093","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5788-3962","authenticated-orcid":false,"given":"Minjie","family":"Luo","sequence":"first","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Wong","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Zelley","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery","family":"Schubert","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth H","family":"Denenberg","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A","family":"Fanning","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gallo","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Netta","family":"Golenberg","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura K","family":"Conlin","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-4202","authenticated-orcid":false,"given":"Kara N","family":"Maxwell","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"},{"name":"Corporal Michael J. Crescenz Veterans Affairs Medical Center , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald B","family":"Wertheim","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea F","family":"Surrey","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Zhong","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett M","family":"Brodeur","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne P","family":"MacFarland","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn M","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"},{"name":"Division of Oncology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia , Philadelphia, PA, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"issue":"1","key":"2024080815365613500_djae102-B1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13073-019-0644-8","article-title":"Clinical utility of custom-designed NGS panel testing in pediatric tumors","volume":"11","author":"Surrey","year":"2019","journal-title":"Genome Med"},{"key":"2024080815365613500_djae102-B2","article-title":"Pediatric somatic tumor sequencing identifies underlying cancer predisposition","volume":"3","author":"MacFarland","year":"2019","journal-title":"J Clin Oncol Precis Oncol"},{"issue":"24","key":"2024080815365613500_djae102-B3","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1056\/NEJMoa1508054","article-title":"Germline mutations in predisposition genes in pediatric cancer","volume":"373","author":"Zhang","year":"2015","journal-title":"N Engl J Med"},{"issue":"7696","key":"2024080815365613500_djae102-B4","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature25480","article-title":"The landscape of genomic alterations across childhood cancers","volume":"555","author":"Gr\u00f6bner","year":"2018","journal-title":"Nature"},{"issue":"11","key":"2024080815365613500_djae102-B5","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1158\/1078-0432.CCR-17-0702","article-title":"Pediatric cancer predisposition and surveillance: an overview, and a tribute to Alfred G. 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