PIK3CA and thyroid cancer, nonmedullary, 2: MAPK activation is considered to be crucial for PTC initiation, through point mutations of the BRAF and RAS genes or gene fusions of RET/PTC and TRK. On the other hand, PI3K/AKT activation is thought to be critical in FTC initiation and can be triggered by activating mutations in RAS, PIK3CA, and AKT1 as well as by inactivation of PTEN, which negatively regulates this pathway.