{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T16:18:44Z","timestamp":1755793124470,"version":"3.44.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Papillary thyroid carcinoma is the most common pathological subtype of thyroid cancer in both children\/adolescents (TCCA) and adults (TCA). TCCA manifests more aggressive and invasive behaviors than TCA, which may be attributed to specific genomic alterations. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To better understand the specific molecular, pathological and clinical manifestations of TCCA, we retrospectively analyzed a cohort of 60 patients with sporadic papillary thyroid carcinoma, including 20 TCCAs and 40 TCAs. Fine-needle aspiration tissue samples from these cases were analyzed using next-generation sequencing. Demographics, ultrasound features, postoperative pathology and radiation exposure history were compared between TCCAs and TCAs. To validate our findings, we integrated data from 28 prior studies, resulting in a larger cohort of 1,483 sporadic TCCAs. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Multiple gene mutations were more prevalent in TCCAs than TCAs (p=0.013), such as <jats:italic>BRAF<jats:sup>V600E<\/jats:sup><\/jats:italic> coexisting with KMT2 family genes or PTEN. Although <jats:italic>BRAF<jats:sup>V600E<\/jats:sup><\/jats:italic> was the most common single nucleotide variant in TCCAs (25%, 5\/20), its prevalence was significantly lower than in TCAs (95%, 38\/40, p&amp;lt;0.0001). <jats:italic>RET<\/jats:italic> oncogenic fusions were detected exclusively in TCCAs, with an incidence of 20% (4\/20). Compared with TCAs, TCCAs were associated with larger tumor diameters (p&amp;lt;0.001), more advanced tumor staging (T3\u2013T4, p&amp;lt;0.001; N2, p=0.002), higher incidence of extrathyroidal extension (TCCA: 25%, TCA: 5%, p=0.036) and more frequent lymph node metastasis (TCCA: 70%, TCA: 27.5%, p=0.0024). Importantly, TCCAs harboring <jats:italic>BRAF<jats:sup>V600E<\/jats:sup><\/jats:italic> alongside other mutations (e.g., <jats:italic>ATM, PTEN<\/jats:italic> or <jats:italic>KMT2<\/jats:italic> family genes) exhibited more severe clinical manifestations, including larger tumors and higher rates of lymph node metastasis, compared with those harboring <jats:italic>BRAF<jats:sup>V600E<\/jats:sup><\/jats:italic> alone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>TCCAs exhibit more aggressive and invasive clinical manifestations than TCAs, particularly in cases with <jats:italic>RET<\/jats:italic> fusions or <jats:italic>BRAF<jats:sup>V600E<\/jats:sup><\/jats:italic> coexisting with other point mutations. Targeted comprehensive molecular profiling may aid in the diagnosis and treatment of TCCA.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1603571","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T04:10:18Z","timestamp":1755231018000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Specific genomic alterations and aggressive clinical features of sporadic thyroid carcinomas in children and adolescents: findings from an in-house cohort study"],"prefix":"10.3389","volume":"16","author":[{"given":"Gongxun","family":"Tan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuguo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoliang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongzhen","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feiju","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenwei","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunhe","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tengxu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuying","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengsheng","family":"Ou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinping","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaolei","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqin","family":"Qian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1530\/erc-22-0293","article-title":"The 2022 who classification of thyroid tumors: novel concepts in nomenclature and grading","volume":"30","author":"Juhlin","year":"2023","journal-title":"Endocr Relat Cancer"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(20)30401-0","article-title":"Global patterns and trends in incidence and mortality of thyroid cancer in children and adolescents: A population-based study","volume":"9","author":"Vaccarella","year":"2021","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.asjsur.2017.10.006","article-title":"Pediatric differentiated thyroid carcinoma: the clinicopathological features and the coexistence of Hashimoto\u2019s thyroiditis","volume":"42","author":"Ren","year":"2019","journal-title":"Asian J Surg"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.20474","article-title":"Papillary thyroid carcinoma of childhood and adolescence: A 30-year experience at the istituto nazionale tumori in Milan","volume":"46","author":"Collini","year":"2005","journal-title":"Pediatr Blood Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2022.1553","article-title":"Update from the 2022 world health organization classification of thyroid tumors: A standardized diagnostic approach","volume":"37","author":"Jung","year":"2022","journal-title":"Endocrinol Metab (Seoul)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2014.0460","article-title":"Management guidelines for children with thyroid nodules and differentiated thyroid cancer","volume":"25","author":"Francis","year":"2015","journal-title":"Thyroid"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2016.08.005","article-title":"Pediatric thyroid cancer: an update from the seer database 2007-2012","volume":"89","author":"Dermody","year":"2016","journal-title":"Int J Pediatr Otorhinolaryngol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s12022-022-09707-3","article-title":"Overview of the 2022 who classification of thyroid neoplasms","volume":"33","author":"Baloch","year":"2022","journal-title":"Endocrine Pathol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2022-0334","article-title":"Evaluation and Management of Pediatric Thyroid Nodules and Thyroid Cancer at a Single Institution after Adoption of the American Thyroid Association 2015 Guidelines","volume":"36","author":"Matalka","year":"2023","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2021.0003","article-title":"Clinical and molecular characterizations of papillary thyroid cancer in children and young adults: A multicenter retrospective study","volume":"31","author":"Guo","year":"2021","journal-title":"Thyroid"},{"key":"B12","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/978-3-030-24100-1_2","article-title":"Next generation sequencing (NGS): A revolutionary technology in pharmacogenomics and personalized medicine in cancer","volume":"1168","author":"Morganti","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(13)60109-9","article-title":"Progress in molecular-based management of differentiated thyroid cancer","volume":"381","author":"Xing","year":"2013","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg2538","article-title":"Radiation-related genomic profile of papillary thyroid carcinoma after the chernobyl accident","volume":"372","author":"Morton","year":"2021","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/jci85271","article-title":"Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers","volume":"126","author":"Landa","year":"2016","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-08-0933","article-title":"High rate of BRAF and RET\/PTC dual mutations associated with recurrent papillary thyroid carcinoma","volume":"15","author":"Henderson","year":"2009","journal-title":"Clin Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2013.0235","article-title":"Concomitant BRAF(V600e) mutation and RET\/PTC rearrangement is a frequent occurrence in papillary thyroid carcinoma","volume":"24","author":"Guerra","year":"2014","journal-title":"Thyroid"},{"key":"B18","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1159\/000490468","article-title":"Ultrasonography and the American thyroid association ultrasound-based risk stratification tool: utility in pediatric and adolescent thyroid nodules","volume":"90","author":"Creo","year":"2018","journal-title":"Horm Res Paediatr"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.09.050","article-title":"Integrated genomic characterization of papillary thyroid carcinoma","volume":"159","year":"2014","journal-title":"Cell"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/genes10090723","article-title":"Thyroid cancer in the pediatric population","volume":"10","author":"Paulson","year":"2019","journal-title":"Genes"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.14310\/horm.2002.1758","article-title":"Differentiated thyroid cancer in childhood: A literature update","volume":"16","author":"Karapanou","year":"2017","journal-title":"Hormones (Athens)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2011.01.154","article-title":"DNA copy number alterations in radiation-induced thyroid cancer","volume":"23","author":"Zitzelsberger","year":"2011","journal-title":"Clin Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djx209","article-title":"Investigation of the relationship between radiation dose and gene mutations and fusions in post-chernobyl thyroid cancer","volume":"110","author":"Efanov","year":"2018","journal-title":"J Natl Cancer Institute"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1998.157","article-title":"Absence of RAS and P53 mutations in thyroid carcinomas of children after chernobyl in contrast to TCA thyroid tumours","volume":"77","author":"Suchy","year":"1998","journal-title":"Br J Cancer"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/lary.24668","article-title":"BRAF V600e does not predict aggressive features of pediatric papillary thyroid carcinoma","volume":"124","author":"Givens","year":"2014","journal-title":"Laryngoscope"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1677\/erc-07-0130","article-title":"BRAFv600e mutation, but not RET\/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer","volume":"15","author":"Romei","year":"2008","journal-title":"Endocrine Related Cancer"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/cells10051082","article-title":"The genomic landscape of thyroid cancer tumourigenesis and implications for immunotherapy","volume":"10","author":"Singh","year":"2021","journal-title":"Cells"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2022.101656","article-title":"Genomic and epigenomic profile of thyroid cancer","volume":"37","author":"Acu\u00f1a-Ruiz","year":"2023","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2005.15.320","article-title":"Braf mutations are uncommon in papillary thyroid cancer of young patients","volume":"15","author":"Penko","year":"2005","journal-title":"Thyroid"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0172","article-title":"Low frequency of BRAFT1796a mutations in childhood thyroid carcinomas","volume":"89","author":"Kumagai","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24935","article-title":"BRAF V600e mutational status in pediatric thyroid cancer","volume":"61","author":"Henke","year":"2014","journal-title":"Pediatr Blood Cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/modpathol.3800252","article-title":"Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma","volume":"18","author":"Rosenbaum","year":"2005","journal-title":"Modern Pathol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.09.050","article-title":"Integrated genomic characterization of papillary thyroid carcinoma","volume":"159","author":"Agrawal","year":"2014","journal-title":"Cell"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2016.0104","article-title":"A national perspective of the risk, presentation, and outcomes of pediatric thyroid cancer","volume":"142","author":"Al-Qurayshi","year":"2016","journal-title":"JAMA Otolaryngology\u2013Head Neck Surg"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13133123","article-title":"Molecular alterations in relation to histopathological characteristics in a large series of pediatric papillary thyroid carcinoma from a single institution","volume":"13","author":"Macerola","year":"2021","journal-title":"Cancers"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15133394","article-title":"The difference in clinical behavior of gene fusions involving RET\/PTC fusions and THADA\/IGF2BP3 fusions in thyroid nodules","volume":"15","author":"Tali","year":"2023","journal-title":"Cancers"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.85.3.6472","article-title":"The ret\/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults","volume":"85","author":"Fenton","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1172\/jci152696","article-title":"Oncogene-specific inhibition in the treatment of advanced pediatric thyroid cancer","volume":"131","author":"Franco","year":"2021","journal-title":"J Clin Invest"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa389","article-title":"Genetic alterations in pediatric thyroid cancer using a comprehensive childhood cancer gene panel","volume":"105","author":"Alzahrani","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1530\/erc-15-0381","article-title":"Are we really at the dawn of understanding sporadic pediatric thyroid carcinoma","volume":"22","author":"Cordioli","year":"2015","journal-title":"Endocrine-Related Cancer"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI144847","article-title":"NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake","volume":"131","author":"Lee","year":"2021","journal-title":"J Clin Invest"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3680","article-title":"Ret revisited: expanding the oncogenic portfolio","volume":"14","author":"Mulligan","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2014.03.032","article-title":"Mechanisms of ret signaling in cancer: current and future implications for targeted therapy","volume":"26","author":"Plaza-Menacho","year":"2014","journal-title":"Cell Signal"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2017.0318","article-title":"Gene fusions in thyroid cancer","volume":"28","author":"Yakushina","year":"2018","journal-title":"Thyroid"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2016.0387","article-title":"Fusion oncogenes are the main genetic events found in sporadic papillary thyroid carcinomas from children","volume":"27","author":"Cordioli","year":"2017","journal-title":"Thyroid"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1501993","article-title":"Biologic and clinical perspectives on thyroid cancer","volume":"375","author":"Fagin","year":"2016","journal-title":"N Engl J Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2005651","article-title":"Efficacy of selpercatinib in ret-altered thyroid cancers","volume":"383","author":"Wirth","year":"2020","journal-title":"New Engl J Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.asjsur.2023.09.049","article-title":"Braf V600e mutation co-existing with oncogenic mutations is associated with aggressive clinicopathologic features and poor prognosis in papillary thyroid carcinoma","volume":"47","author":"Bandoh","year":"2024","journal-title":"Asian J Surg"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-75087-9","article-title":"TERT promoter mutations contribute to adverse clinical outcomes and poor prognosis in radioiodine refractory differentiated thyroid cancer","volume":"14","author":"Tan","year":"2024","journal-title":"Sci Rep"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.674616","article-title":"Tumor mutation burden predicts relapse in papillary thyroid carcinoma with changes in genes and immune microenvironment","volume":"12","author":"Guo","year":"2021","journal-title":"Front Endocrinol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1603571\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T04:10:19Z","timestamp":1755231019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1603571\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":50,"alternative-id":["10.3389\/fendo.2025.1603571"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1603571","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,15]]},"article-number":"1603571"}}