Balkan Journal of Medical Genetics

Although K-ras mutations are implicated in the development of lung cancer, the timing of these mutations in lung carcinogenesis is not understood. Particularly, there have been conflicting reports on whether or not K-ras mutations are present in non-neoplastic or normal-appearing lung tissues obtained from lung cancer patients, which, in the affirmative, would indicate that these mutations rather represent early events in lung carcinogenesis.

The results of our studies demonstrated that K-ras mutations were present in histologically normal tissue surrounding lung tumor [34,35]. They also demonstrated that a genotypically identical K-ras mutation was present in both the histologically normal tissue and matched lung tumor tissue in some cases of lung cancer. In addition, in one case, two mutations were present in the histologically normal tissue but only one mutation was present in the matched tumor and was genotypically identical to one of the mutations found in the normal tissue (see the GGT® AGT mutation in case 4, Table 1).

The K-ras mutation has been reported in non-neoplastic tissues in colorectal and pancreatic cancer. Using sensitive methods, K-ras mutations were detected in histologically normal mucosal tissues adjacent to or distant from colorectal carcinoma [36-38]. K-ras mutations have also been suggested to be preneoplastic events in pancreatic cancer [39-43]. However, in lung cancer, there have been conflicting reports on K-ras mutations in non-neoplastic tissues. Santos et al. [44] investigated a K-ras codon 12 mutation in lung tissues obtained from a patient with squamous cell lung carcinoma and reported that the mutation detected in lung carcinoma was absent from the normal bronchial and parenchymal tissues of that patient, suggesting that malignant activation of K-ras oncogene may be specifically associated with the development of a human neoplasm. Sugio et al. [22] reported that K-ras mutations were infrequent in dysplastic lesions and absent from metaplasia and normal-appearing cells of the lung, suggesting that these mutations are relatively late events in the pathogenesis of lung cancer.

In agreement with the results reported by both Santos et al. [44] and Sugio et al. [22], Urban et al. [45] did not detect K-ras mutations in non-neoplastic peripheral bronchial or parenchymal tissues associated with lung tumors. Finally, in another study by Yakubovskaya et al. [30], K-ras mutations were detected by a sensitive method in up to 60% of samples from normal-appearing lung tissues, 62% of samples from tumor tissues, and 80% of metastasis, obtained from patients with NSCLC. However, the fact that these mutations were present at a very low fraction in these samples suggest that they did not contribute to the development of lung cancer. These results did not agree with those reported in a few other studies. For instance, Westra et al. [23] showed that K-ras mutations were identified in atypical alveolar hyperplasia, a potential precursor from which lung adenocarcinoma arises. In another study of bioptric bronchoscopy specimens from lung cancer patients, Clements et al. [46] showed that, in five of 22 patients, K-ras mutations were found in both malignant and nonmalignant tissues, while in two patients, mutations were found only in the nonmalignant tissue. Our previous study showed that K-ras mutations were detected in both tumor tissue and tumor-adjacent normal-appearing lung tissues in four of eight K-ras mutation-positive cases of lung adenocarcinoma [34]. A recent study by Urban et al. [47] showed that K-ras mutations were detected both in lung tumor and bronchial carina in four of 19 patients (21%) and also only in the bronchial carina but not in the tumor in two of 19 patients (11%). Together, these studies and our study of cells sampled by laser capture microdissection showed that K-ras mutations are present in non-neoplastic lung tissues, including histologically normal tissues, suggesting that these mutations may occur early during the development of lung cancer in some patients with lung adenocarcinoma.