Figure 1.

Oncogenic lesions in the growth factor signaling cascade are depicted (orange boxes) in follicular (left) and parafollicular (right) cell-derived thyroid neoplasms. PTCs are characterized by the presence, in a fraction of cases, of gene rearrangements (RET/PTC or TRK-T) leading to the oncogenic conversion of receptor tyrosine kinases (RTKs) RET or NTRK1. In follicular-cell derived thyroid cancers overall, most of the other mutations target either the “MAPK” (gain-of-function mutations in RAS or BRAF) or the “AKT” (gain-of-function mutations of PI3K or AKT or loss-of-function mutations of PTEN) arm of the RTK signaling cascade. Gene rearrangements of the PPARγ nuclear receptor (to PAX8 or less commonly to CREB3L2) represent another genetic lesion commonly (∼35%) found in FTC; this is not represented here because it appears to be functionally distinct (targeting transcriptional regulation rather than cytoplasmic signal transduction) from the other reported lesions. In most cases, parafollicular cell-derived thyroid cancers (MTC) feature, in a mutually alternative fashion, activating point mutations of RET or RAS. Familial MTC is virtually always caused by germline RET mutations.