Rethinking the Role of Oncogenes in Papillary Thyroid Cancer Initiation

epithelial cells accounts for approximately 1% of all new case of cancer each year and its incidence has increased significantly over the last two decades (Hodgson et al., 2004; Davies and Welch, 2006). Papillary thyroid carcinoma (PTC) accounts for approximately 85% of all cases, and it is responsible for the overall increase in incidence of thyroid cancer. Mortality in PTC is low and the majority of patients can be considered cured after thyroidectomy followed by ablation of thyroid remnant by 131-iodine (Cooper et al., 2009). Molecular studies performed in the last decades, have elucidated in part the molecular mechanisms underlying thyroid cancer initiation and progression. Specific genetic alterations are associated to this thyroid tumor histotype: RET/PTC and TRK rearrangements and BRAF and RAS mutations. The first genetic alteration discovered in PTC and also the most specific was the RET/ PTC rearrangement (Fusco et al., 1987). RET/PTC is a chimeric gene generated by the fusion of the tyrosine kinase domain of the rearranged during transfection gene (RET) to the 5′terminal region of genes that are constitutively expressed in thyroid follicular cells (Pierotti et al., 1992; Santoro et al., 1992, 2006; Nikiforov, 2002). The chimeric proteins generated dimerize in a ligand-independent manner and result in a cytoplasmatic constitutively active tyrosine kinase. The higher frequency of PTC observed in the population exposed to the Chernobyl accident supports a role for the external radiations in the chromosome rearrangements observed in this tumor (Nikiforov, 2006). It has been proposed that the spatial proximity of translocationprone gene loci may favor gene rearrangements. Indeed, proximity between RET and H4, and NTRK1 and TPR has been reported in interphase thyroid nuclei. Thus, in this simplified model, radiations induce chromosome rearrangements and generation of RET/PTC or TRK oncogenes that will be initiator of thyroid carcinogenesis. The role of RET/PTC in thyroid carcinogenesis is supported by experimental evidences generated in cells in culture and in animal models. PCCl3, a differentiated rat thyroid cell line, stably transfected with a RET/PTC3 expressing plasmid undergoes morphological alterations and is no longer TSH dependent for growth (Santoro et al., 1993). Thyroid-specific expression of the RET/PTC1 or RET/PTC3 in transgenic mice induces thyroid tumors with features resembling those of human PTC. These tumors are characterized by nuclear grooves and ground glass cells, continuous slow growth rate, and loss of iodide uptake (Jhiang et al., 1996; Santoro et al., 1996). However, some evidence suggest that RET/ PTC alone is not sufficient to develop thyroid carcinoma, and other molecular events are needed. Thyroid cancer occurs only after a long latency period and only in a fraction of RET/PTC transgenic animals. At beginning, the majority of studies excluded the occurrence of RET/PTC in benign thyroid nodules. In following studies, RET rearrangements have been demonstrated in nodules diagnosed as benign at histology. Ishizaka et al. (1991) have been the first to detected RET/PTC in 21% of follicular adenomas. The use of highly sensitive detection methods contributed to definitively demonstrate that RET rearrangements occurs in a significant fraction of both radiationinduced and sporadic benign nodules (Bounacer et al., 1997; Cinti et al., 2000; Guerra et al., 2011; Marotta et al., 2011a; Sapio et al., 2011). Its presence in benign nodules, raised some queries about the role of RET/PTC in thyroid carcinogenesis. Doubts on the primary role of RET/PTC in thyroid carcinogenesis are also supported by the evidence that some irradiated PTC are composed of a mixture of cells with and without RET rearrangements. In sporadic microcarcinomas and post-Chernobyl PTC interphase fluorescence in situ hybridization (FISH) analysis demonstrated that RET/PTC rearrangements can occur only in a fraction of the cells, indicating that PTC can be composed of a mixture of cells with and without RET rearrangements (Corvi et al., 2001; Unger et al., 2004). These evidences are in favor of a secondary role of RET/PTC which would not be the initiating event in thyroid carcinogenesis. BRAF is a protein-serine/threonine kinases that participate in the mitogenactivated protein kinase (MAPK) cascade (Wellbrock et al., 2004). By modulating the MAPK cascade, BRAF plays a pivotal role in many aspects of cell biology in nearly every cell type. More than 65 different mis-sense BRAF mutations have been detected in human cancer so far (Davies et al., 2002). The BRAF mutation, resulting from the BRAF transversion, is nearly the only mutation of this kinase found in thyroid cancer and the most common genetic mutation in PTC, being detected in about 50% of cases (Kimura et al., 2003; Xing, 2005; Marotta et al., 2011b). This mutation occurring within the activation segment, disrupts the hydrophobic interaction between the glycine-rich loop of the N-terminal region and the activation segment of the kinase domain, and transforms BRAF in a constitutively activated kinase (Davies, et al., 2002; Brummer et al., 2006; Moretti et al., 2009). In the thyroid, this oncogene is restricted to papillary-patterned cancer and it does not occur in Hashimoto’s thyroiditis, benign colloid nodules, thyroid adenomas, or other types of thyroid tumor (Xing, 2007). Rethinking the role of oncogenes in papillary thyroid cancer initiation