This revised study proposes to examine whether a broadrange of dietary and diet-related lifestyle factors affect prostate cancer risk, and is organized around two mechanisms that could mediate effects of diet on prostate carcinogenesis: stimulation of cell growth by steroid hormones, insulin and insulin-like growth factors; and accumulation of somatic mutations caused by oxidative damage. Significant modifications in this revised proposal include more detailed and hypothesis-driven Cross-Project Aims, more accurate estimates of sample sizes, and completion of pilot studies on obesity and glycemic index. Using comprehensive data from the PCPT on diet-related exposures, including serum, anthropometric measures and dietary assessments, we will examine: (1) whether dietary factors that affect each postulated mechanism are associated with risk of prostate cancer and (2) whether the effects of finasteride on prostate cancer risk are modified by diet and diet-related factors. In collaboration with Project 4, we propose to examine associations of dietary and phospholipid fatty acids with the extent, degree and characteristics of inflammation and atrophy in prostate tissue biopsies. Further collaborations are specified in the aims of all other P01 projects, examining risk of prostate cancer as a function of joint associations between: (a) steroid hormones and obesity; (b) obesity and insulin resistance; (c) dairy products and IGFs; (d) antioxidants and inflammation; and (e) antioxidants and polymorphisms in oxidative stress genes. The primary endpoint for all analyses will be the presence or absence of biopsy-detected prostate cancer, which will be characterized either as total cancer or as low- and high-grade disease {Gleason score 2-6 vs. 7-10). Using a nested case-control design, we will have 80% power to detect a minimum odds ratio for total prostate cancer of 1.29 and 1.6 for high-grade disease of 1.86, contrasting highest to lowest quartiles of dietary exposures. This study will yield substantial new information about the relationships of diet with the development of prostate cancer. It may also help to identify diet-related characteristics that could be used to select persons most likely to benefit from finasteride treatment, or to identify dietary modifications or supplements that could be used as adjunct treatment to increase finasteride efficacy.
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