K‐ras mutations in human adenocarcinoma of the lung: Association with smoking and occupational exposure to asbestos

We investigated point mutational activation of the ras genes (K‐ras codons 12, 13 and 61; N‐ras codons 12, 13 and 61; H‐ras codons 12 and 61) in primary, resected lung cancer by dot blotting and oligonucleotide hybridization. K‐ras mutations were found in 14 (29%) of the 48 lung tumour specimens examined, but no N‐ras or H‐ras mutations were found. The highest frequency of K‐ras mutation was observed in adenocarcinoma: 12 of the 21 samples studied (57%) had a mutation, which is one of the highest frequencies reported for lung adenocarcinoma. The commonest type of mutation in these lung tumour samples consisted of transversions: we observed 11, of which 8 (57% of all mutations) were G to T transversions. Most of the 48 patients studied had a history of heavy smoking, either with or without evidence of occupational exposure to asbestos. Statistical analysis revealed‐in addition to the highly significant association between the adenocarcinoma type of lung cancer and K‐ras mutation‐a clear association of K‐ras mutations with heavy life‐time smoking (≥50 pack‐years of cigarette smoking; odds ratio (OR) 4.9, 90% CI 1.2 ‐ 19.5, multivariate analysis). In addition, occupational asbestos exposure showed an elevated, but non‐significant, OR of 2.2 (90% CI 0.6 ‐ 8.7) with the presence of K‐ras mutation. We conclude that the occurrence of K‐ras mutations in adenocarcinoma of the lung is frequent, and that such mutations are associated with heavy life‐time exposure to tobacco smoke, possibly in combination with occupational exposure to asbestos fibres.