A combination of DNA hybridization analyses and tissue sectioning techniques demonstrate that ras gene mutations occur in over a third of human colorectal cancers, that most of the mutations are at codon 12 of the c-Ki-ras gene and that the mutations usually precede the development of malignancy.
On the contrary, genes of ras family were expressed in more limited numbers of cases except for the Ki-ras gene, which was more frequently expressed by cases of the T-cell immunophenotype with a high malignancy grade.
These data suggested that K-ras gene mutations may be correlated with morphology or clinical features in flat elevated cancer, and that flat elevated cancer may originate from a pathway different from adenoma-carcinoma sequence.
Multiplex PCR confirmed the inclusion of both genes in the KRAS2 amplicon in human malignancy, suggesting that either may contribute to the malignant phenotype.
It is suggested that alterations of the p16 gene affect a subset of PILs that contain mutations of the K-ras gene and that these mutations might identify high-risk precursors of the invasive malignancy.
KRAS2 mutations were detected more often in LMP neoplasms than in malignant tumors (P = 0.004) and were detected more often in Stage I/II malignant tumors than in Stage III/IV malignant tumors (P = 0.033), suggesting that LMP tumors with KRAS2 mutations are unlikely to progress to frank malignancy.
The utility of this technique is demonstrated by PCR amplification and sequencing of the K-ras gene and microsatellite PCR analysis of proliferative epithelial lesions in the small ducts of a human pancreas involved by cancer.
We found K-ras gene alteration in 8 lesions (16.0%) out of 50 gastric flat adenomas and no difference in its prevalence between adenoma with or without cancer.
The presence of mutated KRAS2 sequences in the plasma/serum seems to be quite specifically associated with the presence of cancer containing this mutated gene.
These findings suggest that the p53 and K-ras gene mutation patterns are effective markers for the detection of recurrent lung carcinoma in cytologic specimens.Cancer (Cancer Cytopathol)
Although blocking of activated K-Ras may constitute a rational therapeutic concept for this treatment-resistant malignancy, a strategy influencing both oncogenic Ras and the tumor suppressor p53 may be even more promising.
Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16.
At year 3, the data indicated that individuals with KRAS mutations in their baseline premalignant stomach biopsies were 3.74 times as likely to progress to a higher premalignant stage than those who lacked baseline mutations (P = 0.04; C. Gong et al., Cancer Epidemiol.Biomark.Prevy.8:167-171, 1999).
This study describes an advantageous, effective protocol for detecting K-Ras mutations in human stool as a prototype screen for colorectal carcinoma (CRC), the third most common malignancy in the United States.
Our results not only provide genetic support for the idea that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis, but also emphasize the role of repair processes in establishing the mutation spectra that underpin human cancer.
The 96-array constant denaturant capillary electrophoresis provides an opportunity for the high-sensitivity screening of large cancer populations for KRAS exon 1 mutations.