The above general mechanisms of carcinogenesis involving genetic alterations in oncogenes and tumor sup­pressor genes have also been specifically implicated in the development of lung cancer. A large number of these genes have been identified, among them are the ras gene family and the p53 tumor suppressor gene that are the most frequently mutated in many types of tumors including those of the lung [8,9]. Among the most extensively studied oncogenes are those of the ras gene family consisting of the closely-related H-, K-, and N-ras genes, that code for similar 21-kd proteins (ras). The ras proteins are related to the G proteins that bind guanine nucleotides with high affinity and are located at the inner surface of the cell membrane. These proteins have an important role in the signal transduction pathway [7,8]. Activation of the ras genes occurs with specific point mutations at only a few codons including codons 12, 13 or 61. These mutations induce structural changes within the ras proteins leading to an "activated" GTP-bound conformation. The frequencies and types of mutated ras genes have been found to vary among tumors depending on the tissue of origin. For instance, the H-ras gene was most mutated in bladder and breast tumors, while in lung, colon and pancreas tumors, the K-ras gene was the most frequently mutated [8]. Mutations in the K-ras gene have been found in 15 to 50% of adenocarcinoma and large cell undifferentiated carcinoma of the lung [10-14]. Particularly, they have been found more frequently in tumors from smokers (21-35%) than in those from nonsmokers (5-7%), suggesting that they are associated with tobacco smoke exposure [10,14]. They have also been found, but at a lower frequency, in other forms of pulmonary neoplasia, including squamous cell [10-12,14]. The prognostic significance of the presence and specific genotype of K-ras mutations in lung cancer has been the subject of intense study in recent years [8,15-18]. Some studies suggested that patients whose lung tumors contained K-ras mutations are less responsive to therapy, and appear to have a more aggressive disease with shorter disease-free survival and lower overall survival [11,12,14,19]. Other studies suggested that the substitution of the wild type codon 12 amino acid with certain amino acids may be a negative prognostic indicator [20].

Recent insights into the molecular biology of lung cancer show that the progression of this disease is preceded by an accumulation of a series of mutations [21], suggesting that such mutations could provide useful prognostic markers for lung cancer. Although K-ras mutations have frequently been found in lung tumors, the timing of their occurrence in the multistep process of lung carcinogenesis remains poorly understood. Such studies used tissue specimens removed at biopsy or resection [11,17], and cell samples microdissected from embedded lung tissue sections [22,23]. Some of these studies suggest that K-ras mutations occur relatively late in lung cancer development, while other studies indicate that they could represent early events in this process [24]. Here, we summarize the results of a series of studies of K-ras mutations in non-neoplastic tissues and discuss them in relation to the potential role of these mutations as predictive markers for lung cancer.