This proposed study will build upon the extensive epidemiologic database and specimen repository derived from an ongoing bladder cancer study entitled """"""""Genetic Susceptibility to Bladder Cancer: A Molecular Epidemiologic Approach"""""""" (R01 CA74880, applicant: Xifeng Wu). This parent grant includes a multidisciplinary group of researchers using a molecular epidemiologic approach in a case-control study with the common goal of identifying inter-individual differences in susceptibility to tobacco-induced bladder carcinogenesis. Recent evidence has suggested that sensitivity to benzo[(]pyrene diol epoxide (BPDE), the metabolic product of benzo[(]pyrene (B[(]P), a constituent of tobacco smoke, is a constitutional phenomenon and is a risk factor for several tobacco-related cancers such as lung, head and neck, and bladder cancers. There is a need for further elucidation of the molecular targets of BPDE. Loss of chromosome 9p material is one of the most frequent genomic alterations in bladder cancer. In addition, alterations of 9p21 and p16 are frequently seen in the epithelial cells of chronic smokers.
The specific aims of the proposed study are: 1). To determine whether BPDE-induced chromosome aberrations on 9p21 are more common in the cultured peripheral blood lymphocyte (PBLs) of 200 bladder cancer patients than those of 200 controls matched to the cases on sex, age ( 5 years) and ethnicity. Our working hypothesis is that 9p21 BPDE sensitivity may reflect inherited genetic susceptibility of a specific locus to carcinogens in tobacco smoking, that chromosome 9p21 may be the molecular target of carcinogens contained in tobacco smoke, and that individuals with such aberrations are at an increased risk for bladder cancer. 2). To determine frequency of spontaneous 9p21 aberrations occur in cells in urine from 50 cases of bladder cancer patients and whether there is a correlation between level of 9p21 aberrations in lymphocytes and corresponding urine samples. Our working hypothesis is that aberrations in PBLs accurately reflect changes in the target tissue. 3). To assess the associations between the genetic marker and age, sex, cigarette smoking status, and nutrition status by integrating epidemiologic data with the molecular cytogenetic data. These data are being routinely collected in the parent grant. The proposed susceptibility marker may be useful as biomarkers to identify high-risk populations that could then be targeted for intensive smoking-cessation programs and could be enrolled into chemoprevention trials.
| Zhu, Yimin; Yang, Hushan; Chen, Qin et al. (2008) Modulation of DNA damage/DNA repair capacity by XPC polymorphisms. DNA Repair (Amst) 7:141-8 |
| Gu, Jian; Horikawa, Yohei; Chen, Meng et al. (2008) Benzo(a)pyrene diol epoxide-induced chromosome 9p21 aberrations are associated with increased risk of bladder cancer. Cancer Epidemiol Biomarkers Prev 17:2445-50 |
| Zhu, Yimin; Lai, Maode; Yang, Hushan et al. (2007) Genotypes, haplotypes and diplotypes of XPC and risk of bladder cancer. Carcinogenesis 28:698-703 |
