In this Project, we propose to continue the investigation of potentially modifiable nutritional and hormonal risk factors for colorectal cancer, including those that affect survival after the diagnosis of this cancer. This work will use the stored blood and urine samples, archived DNA, repeated questionnaires, and long follow-up in the Nurses' Health Study (1976-2012 with approximately 2,220 incident colorectal cancers), and tumor characteristics using pathology blocks from approximately 1,554 colorectal cancers. We propose to examine 4 inter-related pathways for colorectal cancer: vitamin D, energy balance, inflammation, and melatonin. For aim 1, we propose to examine vitamin D status in relation to hypothesized tumor characteristics, and if preventive actions can be taken through vitamin D supplementation, particularly for women with elevated levels of plasma inflammatory factors. For aim 2, we will examine a comprehensive dietary measure of insulin response (dietary insulin index), clarify the joint and independent effects of adiponectin, and hyperinsulinemia, and identify genes involved in obesity-mediated colon cancer. For aim 3, we propose to better define aspirin chemoprevention of colorectal neoplasia based on COX-2 expression in the incident adenoma, to extend our work to inflammatory markers, and identify genes involved in aspirin-mediated chemoprevention. We will additionally examine the independent effect of these factors on survival following a resection of colorectal cancer. To accomplish this, we propose to link genetic alterations, modifiable factors, and hypothesized pathogenic mechanisms. This Project shares common biological and mechanistic themes with Projects 2, and 3, including the role of vitamin D, and energy balance in relation to cancer incidence and survival, and interacts closely with Project 4 for methodological issues. It also shares with the other Projects a strong scientific and administrative infrastructure provided by Cores A (cohort follow-up and data base maintenance), B (confirmation of cancer and cause of death), C (management of the biospecimens) and D (leadership and data analysis). The findings should enhance understanding of the etiology of colorectal cancer and aid in efforts to reduce incidence and death from this disease.