Distribution of p 53 and Kras mutations in human lung cancer tissues

lung cancer are point mutations in the Kras proto-oncogene 2To whom correspondence should be addressed and in thep53 tumor suppressor gene (5). The critical role of Studies were performed to examine the mutational pattern these alterations in carcinogenesis has been demonstrated in of Kras exons 1 and 2 andp53 exons 5–8 in lung cancer cell culture by co-transfection of mutated p53 and activated tissues from 27 Chinese patients (10 smokers, 17 ras proto-oncogenes into primary rat fibroblasts, leading to non-smokers) using single-stranded conformational polycomplete cellular transformation i vitro (6–8). Various studies morphism and DNA sequencing. K-ras mutations were have shown that chemical carcinogens can selectively induce found in 13/27 tumors (48%); all mutations were clustered specific base pair changes, such as those found in codons 12, in exon 1 and distributed between codons 9 and 32. The 13 and 61 of Kras and in codons 249 and 273 of the p53 frequency and number of patients with K-ras mutations gene (9–11). Using an animal model, 4-(methylnitrosoamino)between smokers and non-smokers were not different, 1-(3-pyridyl)-1-butanone (NNK*), a carcinogen found in except that a high frequency of G→ A transitions (11/ tobacco smoke, induced hamster lung tumors by repeated i.p. 11) was found in non-smokers. Among cell types, Kinjections. Mutations in Kras were found in 50% of the ras mutations were found in 7/13 (54%) squamous cell animals at codon 12, but no mutations were detected in the carcinoma (SC) and 5/12 (42%) adenocarcinoma (AC) p53 gene (12). In another study, 77–94% of tumors contained patients. A → T transversions (all six transversions) were K-ras mutations, but only one tumor had a point mutation in present only in SC. In p53, 18/27 (67%) tumors contained the p53 gene, indicating a distinctive mutation pattern in the mutations in exons 7 and 8, frequently at codons 226, 270, K-rasgene (13). In molecular genetic studies, Krasmutations, 275 and 281. The number of tumors withp53 mutations mostly G→ T transversions in codon 12, have been found in in smokers (70%) and in non-smokers (65%) was similar, 30–60% of adenocarcinoma (AC) and in 10% of squamous and the mutation frequency did not differ except for a cell carcinoma (SC) from smokers (14–16). Mutations in the higher number of G → A (6/7) and T → C (5/6) transitions p53gene are widely distributed throughout exons 4–9 and the in non-smokers. Among cell types, the number of tumors most prevalent mutations are G → T transversions found in with p53 mutations was 9/13 (69%) in SC and 8/12 (67%) tobacco-associated lung cancer (11,17–19). A mixture of highly in AC. The A → G (11/16) transitions and A → C (4/4) mutagenic polycyclic aromatic hydrocarbons (PAH) found in transversions inp53were more frequent in SC than in AC tobacco smoke preferentially attack the guanine base. Strauss (P , 0.04 for A → G; P , 0.02 for A → C). The varying (20) suggested that the predominant G → T transversion occurs mutation patterns in both the Kras and p53genes between in DNA replication, either by a mispairing of the PAHsmokers and non-smokers and among cell types suggest adducted guanine with adenine or by a preferential insertion of that other than cigarette smoke, environmental and dietary adenine opposite the non-instructive modified base. Therefore, factors may also be involved in the genesis of lung cancer analysis of patterns of mutations in these two genes may among these patients. provide clues to the etiology and molecular pathogenesis of