MUTATIONS OF K-RAS ONCOGENE AND ABSENCE OF H-RAS MUTATIONS IN SQUAMOUS-CELL CARCINOMAS OF THE LUNG

Mutations of the K-ras gene have been implicated in the pathogenesis o f human lung adenocarcinomas. In most studies published so far, squamo us cell lung cancers harbored ras mutations only exceptionally or no m utations were detected at all. We have examined 141 lung tumor DNA sam ples for mutations in codons 12, 13, and 61 of K-ras and H-ras oncogen es. A large panel of 118 squamous cell carcinomas was included in the study. For K-ras codon 12, we used a sensitive two step PCR-restrictio n fragment length polymorphism method which detects <1% of mutated DNA in the sample. K-ras mutations were found in 17 tumors (12%; 14 in co don 12 and 3 in codon 13). Among 19 adenocarcinomas, mutation was reve aled in 7 samples (37%). Of these, one sample harbored two point mutat ions in codon 12, Nine mutational events were found in squamous cell c arcinomas (8%, one adenosquamous carcinoma included, all in codon 12). Of four large cell carcinomas, one contained a mutation. Mutant-enric hed PCR products harboring mutations were directly sequenced. Fifteen mutational events were G-->T transversions or G-->A transitions, one w as a G-->C transition, and one sample revealed a frameshift deletion o f one G from codon 12. Similar mutational spectrum was found in both s quamous cell carcinomas and adenocarcinomas, suggesting similar carcin ogenic pathways in both histological types of the tumor. The presence of mutations did not correlate with the stage of the disease. Moreover , we analyzed all samples for mutations in codons 12, 13, and 61 of th e H-ras gene. We found only one mutation in codon 12/ Thus, H-ras muta tions apparently play an inferior role in lung carcinogenesis. We conc lude that mutations of the Kras oncogene can play a role in the develo pment of not only lung adenocarcinomas but also of a subset (about 8%) of squamous cell carcinomas.