We propose to study the p53 gene in lung tumors to determine, for those with a mutation, the nature of that mutation. Tumor material will be obtained from approximately 250 female non-smokers and 250 female smokers. Subjects will be drawn from two completed case-control interview studies: the first of nonsmoking women with lung cancer and the second, of women with adenocarcinoma. Interview data will be used to provide demographic and exposure information, particularly with respect to the extent of indirect (passive) exposure to cigarette smoke: these data will be used to classify the cases for comparison purposes. For the 500 selected cases, a PCR technique will be used to amplify conserved exons of p53 (found to be predominant sites of mutation in tumors studied to date) from paraffin blocks of their tumors. The amplification products will be screened by the method of single strand conformation polymorphism (SSCP) to identify exons containing mutations. Exons showing evidence of mutation will be sequenced to establish the precise nature of the mutation. It is anticipated that approximately 180 of the 500 samples will show p53 mutations. The distribution of type of mutation (specifically the site and nature of the base substitution for point mutations) in p53 in lung tumors in non-smokers will be compared to the pattern for smokers. These comparisons will be used to determine whether the mutational spectrum in lung tumors from non-smokers is consistent with the effects of exposure to a chemical carcinogen similar to cigarette smoke. Separated comparisons will also be made within the subgroup of non-smokers known to be most heavily exposed to environmental (passive) smoke. Finally, the patterns of mutations in each group will be correlated with the sites within the p53 gene that are targeted by the tobacco smoke carcinogen, benzo[a]pyrene.
| Barsky, S H; Sternlicht, M D; Safarians, S et al. (1997) Evidence of a dominant transcriptional pathway which regulates an undifferentiated and complete metastatic phenotype. Oncogene 15:2077-91 |
