If a mutation of c-K-ras 2 gene is an important component in the formation of adenocarcinoma, these results did not confirm the successive development from adenomas with severe atypia to advanced carcinomas as the main route for colorectal carcinogenesis in familial adenomatous polyposis patients.
Our results are the first demonstration of Ha-ras intron D alterations in human tumor tissues and suggest that concurrent mutations at codon 12 and intron D of this gene within the same tumor may contribute to the aggressive behavior of human bladder carcinomas.
In contrast, no point mutation was detected in the 12th, 13th, and 61st codon of the c-Ki-ras and c-Ha-ras gene in 31 primary esophageal carcinomas including those from which TE1 and TE2 cell lines were established.
Mutant c-K-ras genes were detected in about 75% of adenocarcinomas of the pancreas (n = 84); 40% of adenomas (n = 72) and carcinomas (n = 244) of the colon end rectum; 30% of carcinomas of the bile duct (n = 19); 25% of carcinomas of the lung (n = 92), and in lower frequency in other carcinomas, including liver, stomach, and kidney.
Different genes, located as the c-Ha-ras gene on the short arm of chromosome 11, were also found to be deleted suggesting that the deletion of other genes could play a role in aggressiveness of head and neck carcinomas.
We have previously demonstrated that transfection and overexpression of normal or mutated c-Ha-ras genes into a noninvasive human papillary transitional cell carcinoma cell line confer upon these cells an invasive phenotype in vivo with behavior remarkably similar to the clinical behavior of high grade bladder carcinomas.
The absence of ras mutations in the epithelium of primary oral squamous-cell carcinomas is of considerable interest as other work in our Department on Indian cases of oral carcinomas associated with chewing tobacco (quid) revealed that 35% of these had a codon 12, 13 or 61 mutation in Ha-ras.
We found that overexpression of either transfected normal or mutated HRAS genes converted RT-4 cells to express an invasive phenotype remarkably similar in nature to the clinical behavior of high-grade bladder carcinomas.
Using in vitro gene amplification by the polymerase chain reaction (PCR) and mutation detection by the RNAase A mismatch cleavage method, we have examined c-K-ras genes in human pancreatic carcinomas.
Thirty per cent of the carcinomas exhibited heterogeneous staining stronger than that of normal breast, interpreted as increased expression of p21ras protein.
Enhanced Ha-ras expression was documented in 66% of breast and 100% of colon carcinomas as compared with their normal counterparts, with levels in breast carcinomas ranging from 10.1 to 50.4 pg ras p21/micrograms protein and those in colon carcinomas ranging from 18.4 to 51.7 pg ras p21/micrograms protein.
Proteins encoded by cellular ras oncogenes (p21ras) are expressed in a wide variety of malignant tumors, including carcinomas, lymphomas, and neuroectodermal tumors.
We have examined the methylation status of two cellular oncogenes, c-Ha-ras and c-Ki-ras, in primary human carcinomas and the adjacent analogous normal tissues from which the tumors derived.
None of the gastric and seven of the colorectal tumors had mutations of the c-K-ras gene. p53 gene mutations were detected in six gastric carcinomas [two out of 11 intramucosal carcinomas (18.2%) and four out of 11 invasive carcinomas (36.4%)].
C-myc and c-Ha-ras oncoprotein expression was studied by immunohistochemistry and gene detection by in situ hybridization on serial frozen sections of 32 breast lesions (19 benign biopsies and 13 infiltrating carcinomas).
To determine whether atypical epithelium may be precancerous, we examined the DNA sequence of the c-Ki-ras gene at codon 12 in nine cases of CBD concurrent with seven gallbladder carcinomas, one bile duct carcinoma, and one bile duct atypical epithelium.
These results demonstrate that, not only is the timing and frequency of C-KI-RAS activation different between carcinomas originating on the left or right of the colorectum, but also that the biological consequences of such mutations may differ.