p53 Mutations in non-small-cell lung cancers occurring in individuals without a past history of active smoking

Abstract

Summary Accumulating evidence suggests that the p53 gene is a good target for molecular epidemiological studies. We previously reported an association between the presence of p53 mutations and lifetime cigarette consumption. Although over 675 p53 mutations have been reported in lung cancers in the literature thus far, very little is known about the nature of such changes in lung cancers in the absence of a smoking background. In the present study, we therefore analysed 69 non-small-cell lung cancer specimens from individuals without any history of active smoking and identified p53 mutations in 26% of the cases. Statistical analysis of the present cohort of non-smokers also showed absence of significant relationship between p53 mutations and age, sex, histological type or disease stage. Comparison of mutational spectra between the present results in non-smokers and previously reported mutations in smokers clearly demonstrated G:C to T:A transversions to be significantly less frequent in non-smokers than in smokers (OR 5.35, 95% Cl 1.77-16.12). Interestingly, G:C to C:G and G:C to A:T mutations were also observed in tumours of non-smokers at similar frequencies to G:C to T:A mutations, suggesting that these mutations can occur relatively frequently in the absence of active smoking. This study is, to our knowledge, the largest so far analysing a welldefined cohort of non-smokers in a single laboratory.

Novel compound 1,3-bis (3,5-dichlorophenyl) urea inhibits lung cancer progression

“…The loss of tumor suppressor p53 has not only been implicated as an early molecular event in the development of lung cancer in smokers, but also enables the acquisition of drug-resistant and metastatic phenotypes [12]. Activating mutations in intracellular signal transduction pathways like KRAS G12V lead to constitutive activation of proliferative signals which further enhance the aggressive behavior of p53 null lung tumors [13, 14].…”

Molecular epidemiology of smoking and lung cancer

“…Use of mutations in reporter genes, such as HPRT (Bailar, 1999;Hou et al, 1999) or GPA have been used, but it is better to identify mutation rates in cancer susceptibility genes such as p53 (Brennan et al, 1995;Valkonen and Kuusi, 1998) or K-ras (Scott et al, 1997;Slebos et al, 1991;Valkonen and Kuusi, 1998;Yakubovskaya et al, 1995). For p53, it has been reported that there is a dose response relationship between tobacco smoking and p53 mutations in general (Kondo et al, 1996) and for G to T transversions in particular (Kure et al, 1996;Takagi et al, 1998). Women have more G to T transversions than men for similar levels of smoking, even though men have p53 mutations more commonly (Kondo et al, 1996;Kure et al, 1996).…”

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

“…In non-small cell lung cancer (NSCLC) about half of the tumours carry mutations in the p53 gene (Takagi et al, 1998). The prevalent type of mutation is G:C ¡ T:A transversion which is related to DNA adducts of benzo(a)pyrene from cigarette smoking Denissenko et al, 1996).…”