**4. Other Molecular Events in Thyroid Cancer**

A significant number of mutations in thyroid cancer involves encoding genes of the MAPK and PI3K/AKT pathways. Mutated genes that affect these pathways encode the signal transduction molecules RAS, BRAF and NTRK1 and RET receptor tyrosine kinases. These mutations are present in approximately 70% of patients with PTCs and they exhibit particular clinical manifestations as well as specific histopathological characteristics in the tumor level [101–104]. Among FTCs, *RAS* mutations and *PAX8/PPARγ* rearrangements are common [105]. Because PAX8 is important for the development of the thyroid, it has been speculated that the fusion of *PPARγ* and *PAX8* can lead to cancer by activation of aberrant gene transcription [3]. *PAX8/PPARγ* is found in FTCs with a frequency of 30–35% and in a very small percentage of the follicular variant PTCs and follicular adenomas [106–109]. Thyroid tumors harboring *RAS* mutations, most commonly *NRAS* and *HRAS* mutations, include FTCs in 40–50%, PTCs in 10–20% and 20–40% of anaplastic and poorly differentiated carcinomas [110–116]. Because PTCs that harbor *RAS* mutations form neoplastic follicles and no papillary structures, they are known as follicular variant of PTC [101,117]. Benign follicular adenomas have also been found to harbor *RAS* mutations in 20–40%, indicating that they may be precursors of *RAS*-positive FTCs and follicular variant of PTCs [118–121]. Furthermore, BRAFV600E mutation represents 98–99% of all BRAF mutations in thyroid

cancer [122–124]. It accounts for 40–45% of classic PTCs, 30–40% of ATCs, and 20–40% of poorly differentiated thyroid carcinomas [125–128].

Mutations in *BRAF* and *RAS* are thought to represent an early event in the progression of thyroid cancer, given that they are present in poorly and well-differentiated thyroid cancer, as well as in ATCs. On the other hand, additional genetic alterations are usually present in poorly differentiated carcinomas and ATCs; these constitute late events that may be necessary for tumor dedifferentiation. These genetic alterations include mutations in the *TP53* and *CTNNB1* genes and encoding genes of the PI3K/AKT signaling pathway [105]. In 50–80% of ATCs, point mutations that lead to loss-of-function of *TP53* have been identified; these are very rare in well-differentiated thyroid cancer [129,130]. *CTNNB1* mutations occur in approximately 60% of ATCs [131,132].
