The results of extensive analysis of p53 mutations in non-small cell lung cancers (NSCLCs) have revealed that p53 is mutated in 45% of NSCLC with base changes different from those of colon cancer.
Mutations changing the p53 coding sequence were found in 14 of 30 tumor samples (47%), while G:C to T:A transversions which are uncommon in other cancers such as colon cancer were the most frequently observed mutations, in agreement with an earlier report on non-small cell lung cancer in American patients.
The p53 tumor suppressor gene is a possible candidate underlying the syndrome because (a) mutations in the p53 gene are ubiquitous in human cancer, including colon carcinoma and gliomas, and (b) somatic or germ line mutations of the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is characterized by the association of breast and soft tissue tumors.
In this study, we have examined p53 mutations in six cases of colon cancer cell lines, 22 cases of flat-type colorectal tumors, and 27 cases of polypoid-type colorectal tumors using the polymerase chain reaction (PCR) and temperature-gradient gel electrophoresis (TGGE); the latter has recently been developed as a screening method for gene mutations. p53 mutations were observed in four colon cancer cell lines, six flat-type colorectal tumors, and three polypoid-type colorectal tumors, all of which were analyzed by direct sequencing.
Human colon cancer development is associated with the accumulation of mutations and deletions in the suppressor genes DCC, APC and p53 and mutations in the dominant oncogene K-ras, with loss of wild type alleles.
For example, both the RB gene of retinoblastoma and the p53 gene, which is commonly mutated in breast and colon cancer among others, produce proteins involved in distinct steps of cell cycle control, while the nm23 product prevents metastasis.
The resulting T:G mismatches created by this process have been hypothesized to be less efficiently repaired than U:G mismatches formed by deamination of C. We have, therefore, performed the first study to directly compare rates of T:G versus U:G base excision repair at identical sites observed to be mutated in the p53 gene using extracts of human normal colon mucosa and colon carcinoma tissue.
In order to clarify the association between bcl-2 protein (Bcl-2) expression and genetic alteration, we investigated p53 and DCC (deleted in the colon carcinoma gene locus) gene abnormalities in Bcl-2-positive and -negative gastric carcinomas using a polymerase chain reaction/loss of heterozygosity (LOH) assay.
We also assessed the ability of UCN-01 to enhance the cytotoxicity of gamma irradiation in CA46 cells and human colon carcinoma HT-29 cells, both of which are mutant for p53 function.
We also find that induction of wild-type p53 potentiates the cytotoxicity of topotecan, a member of the camptothecin family of drugs that also has clinical activity against colon cancer.
In contrast, a mutant p53 bearing human colon cancer cell line, sw480, lacked spontaneous apoptosis, and upon irradiation neither induction of apoptosis nor increase expression of p53 and WAF-1 were seen.
Differential GADD45, p21CIP1/WAF1, MCL-1 and topoisomerase II gene induction and secondary DNA fragmentation after camptothecin-induced DNA damage in two mutant p53 human colon cancer cell lines.
Moreover, when microinjected into human colon carcinoma cells this peptide restores the transcription activation function to endogenous mutant p53 protein.
Therefore, this model may have some relevance and application to the study of colon cancer in human inflammatory bowel disease, which is not associated with APC mutations or with Ki-ras or p53 mutations.