Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer and identify genetic alterations of potential diagnostic, prognostic and therapeutic significance. Experimental design: The genetic profiles of 583 advanced differentiated and 196 anaplastic thyroid cancers (ATC) generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed. Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared to other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated and anaplastic thyroid cancers. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2 and JAK2 and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro. Three genetically distinct types of ATC are proposed. Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed.
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