Mechanistic insights of thyroid cancer progression.

Differentiated thyroid cancers (DTCs) are primarily initiated by mutations that activate the MAPK signaling cascade, typically at BRAF or RAS oncoproteins. DTCs can evolve to more aggressive forms, i.e., poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC), by acquiring additional genetic alterations which deregulate key pathways. In this review, we focused on bona fide mutations involved in thyroid cancer progression for which consistent mechanistic data exist. Here we summarized the relevant literature, spanning approximately two decades, highlighting genetic alterations that are unquestionable enriched in PDTC/ATC. We describe the relevant functional data obtained in multiple in vitro and in vivo thyroid cancer models employed to study genetic alterations in the following genes and functional groups: TP53, effectors of the PI3K/AKT pathway, TERT promoter, members of the SWI/SNF chromatin remodeling complex, NF2 and EIF1AX. In addition, we briefly discuss other genetic alterations that are selected in aggressive thyroid tumors but for which mechanistic data is still either limited or non-existent. Overall, we argue for the importance that preclinical studies convey for the clinical translation of genomic knowledge of thyroid cancers.