Pancreatic cancer is the fourth leading cause of cancer related death in the U.S. It is a rapidly fatal disease with a 5-year survival rate of 5%. The etiology of pancreatic cancer has not been well defined. Epidemiological and experimental evidence has suggested a role of N-nitroso compounds (NOCs) in pancreatic cancer development. NOCS induce pancreatic tumors in animal models. The K-ras mutation patterns in human pancreatic cancer resemble those in animal models induced by NOCs. However, assessment of dietary NOC intake has been hampered by the lack of a quantifiable tool. To fill in this gap, we have recently developed a database that summarizing NOC values in foods. The current project will utilize this database and estimate the NOC intake from existing food frequency questionnaire data collected from an ongoing case controls study of pancreatic cancer conducted at M.D. Anderson Cancer Center (Supported by NCI grant CA98380). The central hypothesis is that high dietary intake of NOCs alone and in interaction with other genetic and environmental factors modifies the risk of pancreatic cancer. To test this hypothesis, we will compare the NOC intakes in 800 patients with pancreatic adenocarcinoma and 800 healthy controls. We will further explore the interaction between dietary NOC exposure with other environmental risk factors such as cigarette smoking, alcohol consumption, and dietary antioxidant intake. The role of genetic variation in NOC metabolism in pancreatic cancer will be examined by testing single nucleotide polymorphisms (SNPs) of 64 genes involved in nitrosamine metabolic pathway in the same study subjects using the high throughput Sequenom method. The main effects of the genes and their interactions with the exposure variables will be examined by logistic regression analysis. The proposed study is innovative because it will apply a new dietary methodology for NOC estimates, and it will take a pathway- based approach to explore the genetic factor and the gene-exposure interaction in pancreatic cancer etiology. It is a cost effective study by using existing dietary data and DNA samples. Information generated from this study will be valuable in developing novel strategies for the primary prevention of pancreatic cancer.