ROLE OF POINT MUTATION OF THE K-RAS GENE IN TUMORIGENESIS OF B6C3F(1)MOUSE LUNG LESIONS INDUCED BY URETHANE

In order to elucidate the role of point mutation of the K-rns gene in the tumorigenetic process of lung tumors, an experimental model of lun g lesions in mice induced by the administration of methane was used. A total of 135 B6C3F(1) male mice, 6 weeks old, were given methane in t he drinking water at 0, 6, 60, 600 or 1200 ppm, and were then killed a fter varying periods of time. The lung lesions were histologically cha racterized as hyperplasia, adenoma and adenocarcinoma. Point mutations in codons 12 and 61 of the R-ras gene were detected by polymerase cha in reaction-restriction fragment length polymorphism (PCR-RFLP) and co nfirmed by using dideoxy sequencing analysis. K-ras gene mutation was identified in 9 (23.7%) of 38 lesions classified as hyperplasia, 31 (4 6.3%) of 67 adenomas, and 3 (50%) of 6 adenocarcinomas. The most frequ ent mutation was an AT-to-TA transversion at the second base of codon 61 and this pattern accounted for 65% of the three mutant forms observ ed. These results suggest that the point mutation of R-ras gene is inv olved in all stages of mouse lung tumorigenesis, i.e., activation of t his gene can also influence the later stages of lung lesions.