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We aimed at the molecular characterization of PDTC with a specific focus on the identification of potential therapeutic targets. A series of PDTC cases was selected from a multi-institutional network. Fifty-nine samples underwent wide targeted DNA and RNA next-generation sequencing (NGS) testing and immunohistochemical analysis for mismatch repair (MMR) proteins. Gene fusion analysis was enriched by 25 additional samples. Prevalence of MMR protein loss was 11.9%. The most prevalent mutations were in\n                    <jats:italic>NRAS<\/jats:italic>\n                    (25%) and\n                    <jats:italic>TP53<\/jats:italic>\n                    (25%), mutually exclusive.\n                    <jats:italic>TERT<\/jats:italic>\n                    promoter (\n                    <jats:italic>TERTp<\/jats:italic>\n                    ) mutations were detected in 19.6% of cases (10\/51).\n                    <jats:italic>NRAS<\/jats:italic>\n                    -mutated cases were enriched for mutations in genes belonging to the same pathway.\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutated samples lacked\n                    <jats:italic>TERTp<\/jats:italic>\n                    co-mutations, but were associated with mutations in\n                    <jats:italic>PTEN<\/jats:italic>\n                    and in genes related to MMR system and\/or loss of MMR proteins.\n                    <jats:italic>TERTp<\/jats:italic>\n                    mutations were the most prevalent alterations (28%, 7\/25) in a third group that lacked\n                    <jats:italic>NRAS<\/jats:italic>\n                    or\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations. Four cases harbored gene fusions, including two cases harboring the\n                    <jats:italic>TBL1XR1::PIK3CA<\/jats:italic>\n                    fusion that has never been reported in thyroid cancer, so far. In conclusion, PDTC may be genomically segregated in subgroups with specific molecular characteristics. Overall, targetable gene fusions have a prevalence of 9% (4\/42). Moreover, 47% of cases are potential candidates for individualized target therapies since they harbor mutations in genes coding for potentially targetable molecules and\/or have defects in the MMR system.\n                  <\/jats:p>","DOI":"10.1007\/s12022-025-09883-y","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T05:48:45Z","timestamp":1761112125000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["High Prevalence of Potential Molecular Therapeutic Targets in Poorly Differentiated Thyroid Carcinoma"],"prefix":"10.1007","volume":"36","author":[{"given":"Vanessa","family":"Zambelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Orlando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Fornaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Vocino Trucco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Rapa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Napoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Cappia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Daniele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simonetta","family":"Piana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Papotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Volante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"9883_CR1","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1007\/s00268-007-9033-3","volume":"31","author":"EM Sanders Jr","year":"2007","unstructured":"Sanders EM Jr, LiVolsi VA, Brierley J, Shin J, Randolph GW (2007) An evidence-based review of poorly differentiated thyroid cancer. 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