Relatively little is known about the dietary and lifestyle factors that influence survival after a diagnosis of colorectal cancer. In fact, a consensus panel of the American Cancer Society recommended, "Properly conducted studies of the effect of nutrition and physical activity on the prognosis of cancer survivors are urgently needed, and should be a high priority for all academic and research funding agencies." Many of the nutritional and lifestyle factors that are thought to influence colorectal cancer progression (low vitamin D, high insulin, obesity, and physical inactivity) may operate through the vitamin D, inflammatory, and energy balance pathways in the cell. Elucidating the biological explanation for the link between these factors and colorectal cancer would enhance the acceptability of nutrition and exercise as critical for cancer treatment. To address this problem, the current proposal focuses on the investigation of biochemical, genetic, and dietary predictors of colorectal cancer recurrence and survival, with the ultimate goal of reducing mortality. Three inter-related pathways will be studied. For Aim 1, we will examine plasma levels of vitamin D, a vitamin D prediction score, and genetic variation within the pathway, and how these exposures interact with specific molecular alterations. For Aim 2, we will investigate plasma markers of inflammation and genetic variation in inflammation-related genes, in an effort to better understand the link between chronic inflammation and colorectal cancer. In addition, we will explore the interaction between these inflammatory markers and the vitamin D pathway. For Aim 3, we will examine a novel dietary index that estimates long-term systemic insulin exposure, as well as the relationship between members of the insulin-like growth factor pathway and vitamin D. A major strength of this proposal is the ability to examine these plasma, genetic, and dietary factors prospectively, using three large cohorts of colorectal cancer patients with repeated dietary and lifestyle assessments; archived blood, tumor, and DNA specimens; and comprehensive data on prognostic factors and cancer outcomes. By examining these aims, this project will improve the understanding of the mechanisms that underlie colorectal cancer pathogenesis and define practical treatment measures for this difficult disease. Moreover, the current proposal will allow the candidate to gain advanced skills in biostatistics and epidemiology, pursue a focused program in colorectal cancer research, and receive close, long-term mentorship from experienced and successful investigators, promoting her transition to an independent academic researcher. The intense collaboration and vast resources of the Dana-Farber/Harvard Cancer Center, Channing Laboratory, and Harvard School of Public Health provide an ideal environment for the candidate to receive the training and mentorship needed to become a leader in the field of cancer research.