P53 MUTATIONS IN LUNG-TUMORS - RELATIONSHIP TO PUTATIVE SUSCEPTIBILITY MARKERS FOR CANCER

We have screened 108 non-small cell lung tumors for mutational alterat ions in the p53 gene (exons 5 through 8) using polymerase chain reacti on and denaturing gel electrophoresis techniques. Thirty four cases (3 2%) had aberrant band migrations. The following DNA-sequencing step co nfirmed the mutations in all these samples. Seventy-six % of the mutat ions were found at G:C base pairs. Of all the mutations found, 29% wer e GC to AT, 29% GC to TA, 15% AT to GC, 12% GC to CG, and 3% AT to CG. The other mutations (12%) were deletions or insertions of one base pa ir. The frequency of p53 mutations among heavy smokers was higher than in nonsmokers (P = 0.047; odds ratio, 6.75; 95% confidence interval, 0.80-57). We examined p53 mutations in relation to genotypes of GSTmu1 and H-ras1. Our data showed that nearly all heavy smokers with transv ersion mutations were homozygous for the GSTmu1 null allele (10 of 11) . The frequency of such mutations was significantly higher for patient s with two null alleles (10 of 25) than for those with at least one al lele intact (1 of 18) (P = 0.011; odds ratio, 11.33; 95% confidence in terval, 1.29-99.3). This study indicated that rare alleles at the vari able number of tandem repeats region flanking the H-ras protooncogene are negatively associated to the presence of p53 mutations in the tumo rs (P = 0.009).