These findings, coupled with the previous demonstration of 17p allele loss in lung cancer, strongly implicate p53 as an anti-oncogene whose disruption is involved in the pathogenesis of human lung cancer.
Mutation of the p53 gene is the most frequently identified genetic change in human lung cancer; these findings suggest that simple immunohistological methods can provide strong evidence of such mutation.
However, the presence of p53 mutations was not significantly associated with tumor stage, nodal status or sex and was found in all histologic types of lung cancer.
The high incidence of loss of 17p (14 of 21 specimens) appears to be compatible with reports implicating the TP53 gene (at band 17p13) as a frequent site for genetic alteration in lung cancer.
These findings further support the role of inactivation of the p53 gene in the pathogenesis of lung cancer and indicate the role of intronic point mutation in this process.
The mutation frequency (46%) of the p53 gene in tumors carrying mutated ras genes was essentially the same as the overall frequency in lung cancers, suggesting that accumulation of mutations in these two genes in a tumor is a random phenomenon.
These results indicate that mutation of the p53 tumor suppressor gene plays an important role in the development of primary lung cancer, and that nuclear accumulation of p53 protein is a potential prognostic factor in adenocarcinoma of the lung.
None of the mutations were G:C to T:A transversions in the coding strand of the p53 gene, which are the most frequent base substitutions associated with tobacco smoking, and none were found at the hotspot codons described in lung cancer.
We conclude that there are low- and high-expression groups of p53 mutants in lung cancer and that the detection of protein expression in tumor cells by immunocytochemistry and immunoblotting is dependent upon the type of mutation of the p53 tumor-suppressor gene.
A retroviral vector-mediated system was established to allow efficient transduction of the wild-type p53 gene into human lung cancer cell lines H358a (deleted p53) and H322a (mutant p53).
Our results show: (1) wild-type p53 stimulates the transcription of reporter genes with p53CON and RGC in their 5' region while most p53 mutants occurring in human cancers have lost this activity; (2) the R273H mutant retains transcriptional activity for the p53CON sequence but not RGC; (3) some mutants are temperature-sensitive for the transcriptional activity with the p53CON but not the RGC sequence; (4) p53 mutants vary in their ability to inhibit wild-type p53 transactivation but there is no difference between p53CON and RGC sequences; (5) lung cancer cells with endogenous mutant p53 proteins (M246I in H23 cells and R248L in H322 cells) retain transcriptional activity for the p53CON but not the RGC sequence.
Our data suggest that point mutations of the p53 gene are infrequent in pulmonary carcinoids thus contrasting the findings in other histological types of lung cancer, in particular small-cell lung cancer.