High prevalence of potential molecular therapeutic targets in poorly differentiated thyroid carcinoma

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 each other. TERT promoter ( TERTp ) mutations were detected in 21.6% of cases. 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 enriched (up to 32%) 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 7%. Moreover, 38% of cases are potential candidates for individualized target therapies since they harbor mutations/fusions in genes coding for potentially targetable tyrosine kinases and/or have defects in the MMR system.