Activation of the ras genes in malignant and premalignant colorectal tumors.

The activation of ras genes has been established as one of the steps in the process of colon tumorigenesis. These genes are converted into active oncogenes by point mutations in codons 12, 13, and 61, although a more complex way has also been shown, through alteration of gene expression. In order to investigate the spectrum of ras gene mutations, we examined 78 colorectal polypoid adenomas and 76 primary colorectal adenocarcinomas for codon 12 point mutations in K-, H- and N-ras, using a PCR-RFLP assay. K-ras mutations were found in 42.3% (33/78) of adenomas and in 36.8% (28/76) of carcinomas. Statistically significant association (p=0.043) was found between the frequency of K-ras mutations in mixed adenomas larger than 2 cm, compared to smaller mixed adenomas. On the other hand, adenocarcinomas harbored more frequently mutations, when indicating development from adenoma (p=0.016), in higher grade of differentiation (p=0.001) and in females with tumor located proximal to the rectosigmoid (p=0.013). No mutations were found in H-ras. The incidence of N-ras mutations was 1.3% in adenomas and adenocarcinomas (1/78 and 1/76 respectively). Based on our results, we propose the possibility that K-ras-dependent tumor development results in the formation of less aggressive neoplasms, than the process of K-ras-independent carcinogenesis. Our findings and other previous reports indicate that K-ras mutations might be a secondary stress-effect from extrinsic or intrinsic stimulatory factors and that these mutations are not necessarily involved in the malignant transformation of the cell.