RAS Gene and Cancer

A study of colorectal adenomas and cancers in human patients revealed several types of mutations occurring in RAS. The most common mutations affected codon 12, which consists of GGT, and codes for the 12th amino acid of the polypeptide. Most of these mutations resulted in the conversion of GGT, which codes for glycine, to GAT (aspartate), to GTT (valine), and to GCT (alanine) (Zhu et al, 1997). The mutations occurred at the central base of codon 12 and can be summarized as  

The results using oxidatively damaged DNA revealed that adenosine was placed opposite the oxo-G, as shown here  

If this scenario were to occur in a living cell, subsequent cell divisions would result in the maintenance of the abnormal A, and in its coding for a residue of T. The overall scenario is summarized as  

A succinct statement of the big pictures is as follows. The rate of formation of any mutation is a function of the rate of occurrence of the damage to DNA, how fast the damage is repaired, and in the behavior of DNA polymerase when it encounters the lesion during replication. 

One Form of RAS Protein, Called RAC, Uses Superoxide as a Signal 

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Ch. 25). This means that mutations in these proteins that result in alterations in their regulatory properties can lead to oncogenesis. Ras in particular has been implicated in several human cancers [32]. It has been estimated that as many as 30% of all human cancers contain mutations in one of the three Ras genes. While the frequency of Ras mutations in some types of human cancer is very low, its frequency in certain cancers, such as squamous cell carcinoma, lymphatic cancers and colorectal adenocarcinoma, is very high. 

Toxicity and effectivity studies have often been performed in rodent fibroblast cells containing oncogenic H-Ras. However, prenylation of K-Ras B and N-Ras are not as effectively blocked by the farnesyltransferase inhibitors as H-Ras [48] (see below). Thus normal cells may be less sensitive to these drugs because they express K-Ras 4B and N-Ras. In this context it should be noted that H-Ras mutations are relatively uncommon in human tumors [49]. Rather, the K-Ras gene is the most frequently mutated in solid human cancers, whereas N-Ras is prevalent in leukemias. Thus the preclinical evaluation of the farnesylation inhibitors has yet to be critically re-evaluated for trials in humans. 

Ras, a historical proto-oncogene, is frequently mutated in many human cancers, including 90% of pancreatic cancers, 50% of colorectal cancers, 30% of lung cancers, and 15-30% of melanomas [10-12]. There are three Ras genes that encode four family members K-Ras (two alternatively spliced isoforms), H-Ras, and N-Ras. Mutations are most commonly found in K-Ras [13]. These mutations result in impaired GTP hydrolysis, which shifts the equilibrium toward GTP-bound active Ras, and results in constitutive intracellular signaling. 

Zhuang, S.-M., Coclrran, C., Goodrow, T., Wiseman, R.W. Soderkvist, P. (1997) Genetic alterations ofp53 and ras genes in 1,3-butadiene- and 2 ,3 -dideoxycytidine-induced lymphomas. Cancer Res., SI, 2710-2714... 

Levine, A.E. Chakrabarty, S. (1992) Response of FR3T3 cells transformed by Ha-ras oncogene and epidermal growth factor gene to differentiation induction by A A -dimethylformamide. Int. J. Cancer, 50, 653-658... 

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