GENETIC ALTERATIONS IN P53 AND K-RAS IN LUNG-CANCER IN RELATION TO HISTOPATHOLOGY OF THE TUMOR AND SMOKING HISTORY OF THE PATIENT

The inactivation of the p53 suppressor gene and the activation of the ras proto-oncogenes are frequent events in non-small cell lung cancer as well as in many other solid neoplasms in man. Somatic mutations in exons 5-8 of the p53 gene were detected in 59% (30/51) of the squamous cell carcinoma and in 38% (14/37) of the adenocarcinoma tumors using GC-clamped, non-radioactive denaturing gradient gel electrophoresis (D GGE). The mutations in the exons 5 and 8 represented larger proportion of the alterations in squamous cell carcinoma tumors (p=0.04; Fisher' s exact test, two-tailed); in the adenocarcinoma tumors, mutations wer e most common in the exon 7 of p53. Most of the identified mutations ( 25/39; 64%) are predicted to cause an amino acid substitution. Mutatio ns leading to the premature termination of translation were more frequ ent in adenocarcinoma (6/14) than in squamous cell carcinoma (3/30) tu mors (p=0.02). In adenocarcinoma, also base substitutions in the K-ras gene were detected more often (18/37; 49%) than in squamous cell carc inoma (p<0.01). However, a mutation both in p53 and Kras was detected in only 4% of the lung tumors which does not support importance of co- operation between the genes in vivo. Mutations in p53 and K-ras did no t correlate with tumor differentiation in either histological type. In squamous cell carcinoma, mutations in p53 showed relation to pack yea rs smoked whereas in adenocarcinoma, mutations in the K-ras gene were associated with cigarette consumption. G to T transversion was the mos t common type of base substitution in both genes (31% in p53 and 53% i n K-ras).