Recurrence is the hallmark of bladder cancer. There is limited information on factors that can affect tumor recurrence. Building upon the epidemiologic and molecular genetic findings from our funded research on bladder cancer (NCI RO1 CA74880). In this translational research, we propose to evaluate epidemiologic profiles and a panel of susceptibility markers on the influence of bladder cancer recurrence in 480 prospectively identified patients with superficial bladder cancer. Fifty percent of these patients are expected to develop recurrence over 4 years of follow up. We will focus on assessing detailed tobacco smoking exposure over time and a panel of genotypic susceptibility markers related to tobacco carcinogen metabolism, DNA repair, disease progression, and nicotine addiction. We hypothesize that patients with recurrence exhibit higher exposure profiles, and may be more likely to exhibit susceptible genotypes than patients who do not develop a recurrence. The following are the specific aims: 1) To compile comprehensive epidemiologic profiles on all patients at registration and on follow-up with specific emphasis on the continued smoking status of patients from the time of diagnosis of their initial primary to development of recurrence.
This aim will test the hypothesis that continuing exposure to tobacco and specific dietary patterns such as high fat intake and low vegetable and fruit intake may be associated with increased for recurrences. 2). To determine the frequencies of polymorphisms in genes that are related to DNA damage and/or repair, such as myeloperoxidase (MPO), N-acetyltransferase (NAT)1, NAT2, glutathione-S-transferase (GST) M1, GSTT1, GSTP1, XRCC1, XPD, XRCC3, and p53. Our hypothesis is that patients with adverse genotypes are at greater risk for the development of recurrences, because of higher internal dose of tobacco carcinogens through increased activation or decreased detoxification and/or because of sup-optimal DNA repair capacity. 3) To determine the frequencies of polymorphisms in the cancer invasion/progression related genes E-cadherin, cyclin D1 (CCND1), metalloproteinase-1 (MMP-1 and MMP-9), and vascular endothelial growth factor (VEGF). Our hypothesis is that patients with adverse genotypes of these genes are at greater risk for bladder cancer recurrence. 4) To determine the relationship between baseline and follow-up smoking status and potential genetic markers for nicotine-dependence (genetic polymorphisms in dopamine receptor genes, DRD2A1 and -B1 and dopamine transporter gene SLC6A3-9) and to correlate these findings with known predictors of smoking cessation and nicotine dependence, such as history of depression and alcohol use.
This aim i s relevant to recurrence of bladder cancer since nicotine addiction provides the link through which smokers are repeatedly exposed to carcinogenic elements associated with tobacco consumption. There is an important implication to this project in identification of high risk subgroups of bladder cancer patients who can be more intensively screened and treated for recurrence prevention. This project will have interactions with SPORE Administrative, Pathology and Biostatistics Cores.
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