The objectives of this proposal are to characterize the patterns of p53 gene mutations in bladder cancer, and to correlate these genetic abnormalities with epidemiological data including environments, exposure to certain carcinogens and family history of cancer.
Our specific aims are: 1) to validate the detection of mutant p53 encoded proteins by comparing different techniques; and 2) to assess the association between environmental exposures and p53 mutations. We will expand our study to other tumor suppressor genes, including retinoblastoma susceptibility gene (RB), nm23, DCC, and the candidate tumor suppressor gene in 3p. In a three-year study period, 220 patients with transitional-cell bladder cancer and 220 controls will be recruited at Memorial Hospital. An epidemiological questionnaire will be used to collect information on cigarette smoking, occupational exposure and other risk factors. Tumor specimens will be collected. We will assess phenotypic and genotypic patterns of p53 gene, and correlate patterns observed by immunohistochemistry (IHC) techniques with those using polymerase chain reaction (PCR-SSCP) cloning and sequencing techniques. We will examine the hypothesis that bladder cancer patients with p53 mutations and without p53 mutations are etiologically distinct groups; we will use PCR- SSCP methods to distinguish these groups. Using a case-control study design, we will estimate the odds ratios of the risk factors for each of the distinct bladder cancer groups (i.e. mutant p53 and non-mutant p53 patients). We will correlate specific intragenic p53 mutations with certain carcinogens in a group of patients with a spectrum of p53 mutations. We will describe whether """"""""carcinogen-induced"""""""" mutations are common in patients with environmental exposures including cigarette smoking and occupational exposures. Additionally, we will characterize patterns of p53 mutations for patients with both family history of cancer and environmental exposures. The wide spectrum of p53 mutations make the p53 gene much more suitable for identifying possible carcinogens. Bladder cancer with both """"""""induced"""""""" and """"""""spontaneous"""""""" patterns of p53 mutations, as well as with multiple risk factors (i.e., cigarette smoking and occupational exposures), is an attractive model for transferring molecular technology to cancer epidemiology. To our knowledge, an in- depth study of this nature has not yet been carried out. This proposed study may serve as a model for bridging the gap between biotechnology and cancer epidemiology.
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