This project aims to identify dietary, reproductive and genetic factors related to bladder cancer in two large ongoing prospective cohorts of men and women. Risk factors of bladder cancer are largely unknown but this important disease is likely to be largely preventable, given the large regional variations in incidence rates. Compared to some other cancers, bladder has received little attention and support. There are exciting opportunities to improve the understanding and ultimately prevention of this disease. We propose to study bladder cancer in the Nurses? Health Study and the Health Professionals Follow-up Study. By 2004, we project that 562 men and 391 women will be diagnosed with bladder cancer in these two cohorts. We will conduct prospective analyses using both cohorts, and nested case-control analyses among members who have provided blood, cheek cells, or toenails. We propose to obtain tumor specimens from participants with bladder cancer to examine specific tumor alterations (specifically p53 overexpression). We propose to examine dietary factors in detail among women who completed the initial dietary questionnaire in 1980; the ?diet? cohort we will have 312 women with bladder cancer. Selenium and arsenic levels will be assessed from toenails of over 500 men and women with bladder cancer and will be compared to 500 controls selected from the same cohorts. We will also examine specific dietary interactions with three polymorphic genes that have been previously related to bladder cancer risk (NAT1, NAT2 and GSTM1). We will use p53 overexpression as an alternative endpoint to determine if specific dietary factors can predict p53 mutations in bladder cancer. Stratified analyses and multiple logistic regression will be used to control for potential confounding by age, smoking, and other relevant nutrients or foods.