Ras Mutations In Thyroid Cancer

A metastatic tumor is the end result of a complex series of steps involving multiple gene products. Work performed over the past decade has identified a number of gene products with putative roles in the initiation and progression of thyroid tumorigenesis. Mutations in Gsa (gsp) and the TSH receptor have been identified in hyperfunctioning adenomas. Ras mutations are prevalent in follicular carcinomas (see below). Mutations in ret, trk and met were identified in papillary carcinomas. Aberrant DNA methylation, leading to loss of expression of the p16 tumor suppressor gene, has been described in both types of cancer. Finally, mutations in p53 appear to play a role in the final dedifferentiation process. The reader is referred to several excellent recent reviews regarding the molecular basis of thyroid cancer (Jhiang, 2000; Gimm, 2001; Puxeddu et al., 2001; Fagin, 2002).

Early reports revealed that Ras mutations were particularly prevalent in benign follicular adenomas and follicular carcinomas, where estimates ranged as high as 50% (Lemoine et al., 1990; Namba et al., 1990; Suarez et al., 1990; Shi et al., 1991; Farid, 1994). The frequency of Ras mutations was initially reported to be similar in benign adenomas and follicular carcinomas, suggesting that Ras played an early role in thyroid transformation. However, more recent studies suggest that Ras mutations are less frequent than was first reported, occurring with an overall frequency of 16-19% (Esapa et al., 1999; Vasko et al., 2003). These studies also revealed a higher frequency of Ras mutations in follicular carcinomas versus adenomas, consistent with a role for Ras in malignant progression. According to recent data, mutations in codon 61 of N-Ras are the most frequent Ras mutation found in thyroid tumors (Nikiforova et al., 2003; Vasko et al., 2003). Besides Ras mutations, a significant proportion of follicular carcinomas exhibit a specific chromosomal translocation that fuses the coding regions for the paired and homeobox binding domains of the Pax-8 transcription factor to the DNA and ligand binding, dimerization and transactivation domains of (Martelli et al., 2002). Interestingly, follicular carcinomas harboring both Ras mutations and the translocation are extremely rare. This indicates either that both changes activate similar signaling pathways or that follicular carcinomas are comprised of at least two distinct tumor types that arise by different mechanisms (Nikiforova et al., 2003).

Although Ras mutations are infrequent in papillary thyroid carcinomas, somatic mutations in B-Raf were recently identified in these tumors (Kimura et al., 2003; Cohen et al., 2003). B-Raf mutations were discovered in a wide range of human tumors only last year (Davies et al., 2002; Rajagopalan et al., 2002). Intriguingly, mutations in B-Raf were found in cancers that typically harbor Ras mutations, such as malignant melanomas, colorectal tumors and ovarian cancers. The most frequent B-raf mutation (V599E) results in the insertion of an acidic residue close to a site of activating phosphorylation in the kinase domain. Recombinant B-RafV559E exhibits increased kinase activity, suggesting constitutive activation of signaling pathways similar to those activated by Ras. Moreover, unlike activated Raf-1 mutants that stimulate transformation through an autocrine mechanism involving Ras, the effects of

B-RafV559E on cell transformation were Ras-independent (Davies et al., 2002). The same B-Raf mutation has now been shown to be the most common genetic change in papillary thyroid carcinomas (Kimura et al., 2003). These results are striking for several reasons. First, there are three mammalian Raf proteins: Raf-1, A-Raf and B-Raf. While Raf-1 is ubiquitously expressed, A- and B-Raf exhibit a more restricted pattern of expression. Intriguingly, B-Raf is expressed in neuronal, neuroendocrine and endocrine cells. Of further interest with regard to thyroid cells, Raf proteins are important sites of integration between signals activated by Ras and cAMP. Cyclic AMP impairs the activation of Raf-1 by serum growth factors and Ras (Figure 2). In contrast, cAMP stimulates B-Raf activity (Erhardt et al., 1995; Vossler et al., 1997; Busca et al., 2000). Therefore, it is perhaps not surprising that melanoma cells harbor B-Raf mutations given their regulation by stimulating hormone and related proopiomelanocortin-derived peptides that upregulate intracellular cAMP. Similarly, the identification of B-Raf mutations in thyroid tumors is particularly interesting given the growth promoting effects of chronic TSH stimulation. Despite the high frequency of Ras mutations in colorectal cancers, B-Raf mutations were found only in tumors without Ras mutations. In agreement with these results, no overlap was seen between mutations in Ras and B-Raf in papillary thyroid carcinomas (Kimura et al., 2003). These results provide strong support for the notion that B-Raf and Ras mutations are equivalent in their tumorigenic effects. Finally, RET/PTC oncogenes also signal partly through Ras (Barone et al., 2001; Castellone et al., 2003) and possibly through PDK-1 (Kim et al., 2003), a protein kinase that is also activated downstream from Ras. Strikingly, there appears to be no overlap between papillary carcinomas harboring RET/PTC, B-Raf and Ras mutations, which together account for two thirds of all papillary carcinomas. These findings underscore the significant contribution of Ras-mediated signaling pathways to thyroid tumorigenesis. In the following sections, I review what is known regarding the role of endogenous Ras, and the consequences of sustained Ras activity in thyroid cells.

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