{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T13:36:58Z","timestamp":1792417018021,"version":"4.4.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"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>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Thyroblastoma is a rare and highly aggressive embryonal thyroid malignancy typically associated with DICER1 alterations. However, DICER1-wildtype cases remain poorly characterized at the molecular level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We report a case of aggressive thyroblastoma in a 62-year-old male, negative for canonical DICER1 RNase IIIb mutations. Comprehensive genomic profiling was performed using Oxford Nanopore long-read sequencing, followed by integrative bioinformatic and pathway-level analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Molecular analysis revealed an alternative oncogenic signature characterized by an EIF1AX p.Lys3_Lys5dup duplication, TERT alterations (promoter C228T and coding p.C42R), and an AGK\u2013BRAF fusion predicted to drive constitutive MAPK\/ERK signaling. Functional enrichment analyses highlighted dysregulation of translational initiation, telomere maintenance, and mitogenic pathways, alongside potential immune-escape mechanisms linked to DUX4 activation. Clinically, the tumor exhibited a triphasic morphology, extensive locoregional infiltration, pulmonary metastases, and only transient response to chemotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings expand the molecular spectrum of thyroblastoma beyond the canonical DICER1-driven paradigm and suggest that DICER1-wildtype cases may represent a distinct biological subgroup. The identification of alterations affecting TERT and MAPK pathways highlights potential therapeutic vulnerabilities and supports the clinical value of comprehensive genomic profiling in ultra-rare thyroid malignancies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1747919","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T04:32:10Z","timestamp":1776832330000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Genomic profiling of a DICER1-wildtype thyroblastoma reveals AGK-BRAF fusion, EIF1AX duplication, and TERT promoter mutations: integrated genomic and pathway analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Alberto","family":"Gualandi","sequence":"first","affiliation":[{"name":"Pathology Unit, Istituto Nazionale Tumori IRCCS \u2013 Fondazione G. Pascale","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda","family":"Picozzi","sequence":"additional","affiliation":[{"name":"Sarcoma and Rare Tumors Unit, Istituto Nazionale Tumori IRCCS \u2013 Fondazione G. Pascale","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabella","family":"Di Mauro","sequence":"additional","affiliation":[{"name":"Pathology Unit, Istituto Nazionale Tumori IRCCS \u2013 Fondazione G. Pascale","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susi","family":"Pelotti","sequence":"additional","affiliation":[{"name":"Unit of Legal Medicine, Department of Medical and Surgical Sciences, University of Bologna","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imma","family":"D\u2019Arbitrio","sequence":"additional","affiliation":[{"name":"Pathology Unit, Istituto Nazionale Tumori IRCCS \u2013 Fondazione G. Pascale","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Science and Technology, Parthenope University of Naples","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Cannella","sequence":"additional","affiliation":[{"name":"Sarcoma and Rare Tumors Unit, Istituto Nazionale Tumori IRCCS \u2013 Fondazione G. 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Pascale","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annarita","family":"Peddio","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University Federico II","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerardo","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Pathology Unit, Istituto Nazionale Tumori IRCCS \u2013 Fondazione G. Pascale","place":["Naples, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Tafuto","sequence":"additional","affiliation":[{"name":"Sarcoma and Rare Tumors Unit, Istituto Nazionale Tumori IRCCS \u2013 Fondazione G. 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