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Incidence and Possible Clinical Significance of K-ras Oncogene Activation in Adenocarcinoma of the Human Lung¹

Divisions of Experimental Therapy and Clinical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam [S. R., R. J. C. S., S. G. E., W. J. M.]; Department of Medical Biochemistry, State University of Leiden, Sylvius Laboratories, Wassenaarseweg 72, 2333 AL Leiden [A. J. M. B., J. L. B.]; and Departments of Pathology and Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 LM Nieuwegein [S. Sc. W., P. Ch. v. B.]; The Netherlands

47 tumor samples, 45 of which were obtained at thoracotomy for nonsmall cell lung cancer were examined for mutational activation of the oncogenes H-ras, K-ras, and N-ras. A novel, highly sensitive assay based on oligonucleotide hybridization following an in vitro amplification step was employed. ras gene mutations were present in nine of 35 adenocarcinomas of the lung (all K-ras), in two of two lung metastases of colorectal adenocarcinomas (1 x K-ras, 1 x N-ras) and in one adenocarcinoma sample obtained at autopsy (H-ras). All K-ras and H-ras mutations were in either position 1 or 2 of codon 12, while the N-ras mutation was in position 2 of codon 61.

The potential clinical significance of K-ras activation was analyzed using the combined results of this and of our earlier study (S. Rodenhuis et al., New Engl. J. Med., 317: 929–935, 1987). Lung adenocarcinomas with K-ras mutations tended to be smaller and were less likely to have spread to regional lymph nodes at presentation. With a median follow up of 10 months, survival data are still immature. None of six adenocarcinomas of nonsmokers had a K-ras mutation and only one of four who had stopped smoking more than 5 years before. We conclude that mutational K-ras activation is present in about a third of adenocarcinomas of the lung and that the mutational event may be a direct result of one or more carcinogenic ingredients of tobacco smoke. Studies involving larger numbers of patients are required to confirm the association of K-ras activation with smoking and the inverse relation with tumor progression.

¹ Supported by Grants NKI 87-15 and IKW 86-93 of The Netherlands Cancer Foundation K. W. F. and by a grant from Centocor, Leiden.

² To whom requests for reprints should be addressed.

Received 3/30/88. Revised 7/ 1/88. Accepted 7/13/88.

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