*2.2. Gene Fusions*

Fusion genes are common driver mutations described in both hematopoietic and solid tumors [41]. They usually involve a driver gene, which expresses a receptor tyrosine kinase (e.g., RET) or its downstream kinase (e.g., BRAF), and a partner gene (e.g., NCOA4). If in physiologic state most of these kinases require the ligand to induce their dimerization, these rearrangements are capable to induce a ligand-independent dimerization and a deregulated kinase activity [42]. In the past, all the tumorigenic effects were considered as consequence of a non-controlled expression of the driver gene; however, new evidence suggests that also the partner gene may play a crucial oncogenic role [43].

Although fusion genes have been extensively described in thyroid cancer, their prevalence is lower compared to other solid tumors [41]. PDTC harbors gene fusions in 10–14% of cases while ATC in 3–5% [44] (Table 2). Interestingly, when present, fusions usually involve the same few oncogenes. RET fusions are the most common, mainly CCDC6-RET (RET/PTC1) and NCOA4-RET (RET/PTC3), while NTRK, ALK and BRAF fusions are quite rare (Table 2) [44]. Recently, Nikitski et al. developed a mouse model of STRN-ALK fusion gene that was capable of inducing PTC, PDTC and ATC foci [45]. This model revealed the presence of two clusters of PDTC with specific cell morphology, immunohistochemical characteristics and different levels of expression of thyroid differentiation markers [45].


**Table 2.** ATC and PDTC genetic landscape: gene fusions.

Although rare, gene fusions could represent precious targets for targeted therapies. Moreover, any histotype of thyroid cancers with gene fusions has recently been proposed as a discrete group with specific histologic characteristics such as multinodular growth and extensive fibrotic features. For this reason, they have been named "kinase fusion-related thyroid carcinomas" [46].
