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<p>Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid cancer with aggressive clinical course and peculiar clinical/pathological characteristics but lacking effective therapeutic options, when surgery is not curative. 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 <i>NRAS</i> (25%) and <i>TP53</i> (25%), mutually exclusive. <i>TERT</i> promoter (<i>TERTp</i>) mutations were detected in 19.6% of cases (10/51). <i>NRAS</i>-mutated cases were enriched for mutations in genes belonging to the same pathway. <i>TP53</i>-mutated samples lacked <i>TERTp</i> co-mutations, but were associated with mutations in <i>PTEN</i> and in genes related to MMR system and/or loss of MMR proteins. <i>TERTp</i> mutations were the most prevalent alterations (28%, 7/25) in a third group that lacked <i>NRAS</i> or <i>TP53</i> mutations. Four cases harbored gene fusions, including two cases harboring the <i>TBL1XR1::PIK3CA</i> 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.</p>

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High Prevalence of Potential Molecular Therapeutic Targets in Poorly Differentiated Thyroid Carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月22日

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  • Vanessa Zambelli,
  • Giulia Orlando,
  • Marta Fornaro,
  • Giulia Vocino Trucco,
  • Ida Rapa,
  • Francesca Napoli,
  • Susanna Cappia,
  • Lorenzo Daniele,
  • Simonetta Piana,
  • Mauro Papotti,
  • Marco Volante

摘要

Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid cancer with aggressive clinical course and peculiar clinical/pathological characteristics but lacking effective therapeutic options, when surgery is not curative. 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 NRAS (25%) and TP53 (25%), mutually exclusive. TERT promoter (TERTp) mutations were detected in 19.6% of cases (10/51). NRAS-mutated cases were enriched for mutations in genes belonging to the same pathway. TP53-mutated samples lacked TERTp co-mutations, but were associated with mutations in PTEN and in genes related to MMR system and/or loss of MMR proteins. TERTp mutations were the most prevalent alterations (28%, 7/25) in a third group that lacked NRAS or TP53 mutations. Four cases harbored gene fusions, including two cases harboring the TBL1XR1::PIK3CA 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.