K-ras Mutations Are a Relatively Late Event in the Pathogenesis of Lung Carcinomas

We investigated preneoplastic lesions associated with lung cancer to determine at what stage in lung carcinogenesis K-ras mutations appear. We selected six archival lung cancer resection cases that had ras mutations. We precisely microdissected 74 relevant areas from paraffin-embedded sections. K-ras mutations at codons 12, 13, and 61 were determined by the designed restriction fragment length polymorphism method using mismatched nested primers and confirmed by direct sequencing. All samples of invasive and metastatic cancers had K-ras mutations, as did four of five lesions of noninvasive cancer. Mutations were detected in only 1 of 12 dysplastic lesions and were absent from hyperplastic and normal-appearing cells. In all cases, the specific point mutation and the mutational pattern in the tumors, metastases, and the corresponding noninvasive lesions were identical. These results indicate that K-ras mutations arise relatively late in the pathogenesis of lung cancer and may be associated with the appearance of the malignant phenotype.