Ras Family Oncogenes

Activating point mutations in three human ras genes (i.e., Harvey ras [H-ra.iJ on chromosome 11, Kirsten ras [K-ra.i] on chromosome 12, and N-ras on chromosome 1) have been demonstrated in numerous tumors, including thyroid tumors. Approximately 40% to 50% of colon cancers, more than 80% of pancreatic cancers and cholangiocarcino-mas, and 30% to 40% of lung cancers harbor specific ras mutations.32 34 Ras encodes a small protein, p21, of 21,000 D that has no intrinsic GTPase activity. p21 forms a complex with a GTPase-activating protein, GAP, that enhances the GTPase activity of p21 more than 4000 times. This GAP-induced GTP hydrolysis is reduced by a factor of 1000 by mutant ra.v-encoded proteins when the mutations occur at codon 12, 13, or 61.

Although ras mutations in colon, pancreatic, and other cancers are mainly restricted to one or two different ras genes, some researchers dealing with thyroid tumors have found all three ras genes (on three different chromosomes) mutated at different sites (Table 30-3).8,35"40 Although some groups mainly found H-ra.i mutations, others predominantly demonstrated N-ras mutations (see Table 30-3). Some of these differences may be explained by variations in methodology, with possible errors generated when only hybridization techniques were applied. Hybridization techniques can yield false-positive and false-negative results, as demonstrated by Chen and Viola.41 Even in cases of comparable technical procedures, results vary significantly between groups. The prevalence of ras mutations in thyroid tumors therefore remains questionable. Most studies have shown that the prevalence of ras mutations was not significantly different in benign and malignant thyroid tumors, nor was it different in tissues from patients living in low- or high-iodine areas (Table 30-4).8-30

Exposure to low-dose therapeutic radiation seems to increase the K-ra.v mutations in histologically normal thyroid tissues and in tissues from thyroid tumors. Fogelfeld and colleagues42 demonstrated an increase in K-ras mutations in thyroid tumor tissue from 0% (0 of 18 patients) to 62% (8 of 13 patients) after radiation therapy. Confirmation of this interesting finding is pending. Nevertheless, some of the differences in the prevalence of ras mutations in thyroid tumors may be caused by regional differences in environmental conditions,34 similar to aflatoxin-induced hepatocellular carcinomas occurring in Asia but not in Europe.

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