Mutational Activation of the K-ras Oncogene

To define the role of cellular oncogenes in human cancers, we studied the prevalence of mutational activation of ras oncogenes in untreated non-small-cell lung cancer. Genomic DNA was extracted from 39 tumor specimens obtained by thoracotomy and was examined for activating point mutations in codons 12, 13, and 61 of the H-ras, K-ras, and N-ras genes. A novel, highly sensitive assay based on oligonucleotide hybridization following an in vitro amplification step was employed. The K-ras gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No ras gene mutations were observed in 15 squamous-cell carcinomas, 10 large-cell carcinomas, 1 carcinoid, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small-cell carcinoma. An approximately 20-fold amplification of the unmutated K-ras gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma. We conclude that mutational K-ras activation may be an important early event in the pathogenesis of adenocarcinoma of the lung but that amplification of ras genes or mutational activation of H-ras or N-ras does not play a major part in non-small-cell lung cancer. (N Engl J Med 1987; 317:929–35.), DESPITE recent advances in our understanding of the molecular mechanisms that give rise to malignant behavior of cells, the role of known oncogenes in human cancer remains largely conjectural.¹ Oncogenes are derived from normal genes (“proto-oncogenes”) that are highly conserved in evolution and that code for proteins having important roles in normal cellular processes, such as the regulation of gene expression or growth-signal transduction. Certain events may lead to structural abnormalities in or around these genes that make them contribute to the process of malignant transformation (“activation”). The most frequent mechanisms of this activation of proto-oncogenes in human cancers are….