Pancreatic cancer is the 4 leading cause of cancer mortality in the US, and has a dismal median survival of 4.1 months. This high case fatality rate challenges research on the identification of risk factors that could be used for early detection. Pancreatic cancer is associated with rare genetic syndromes, but no specific candidate genes for susceptibility to pancreatic cancer have been identified in the general population. However, strong and consistent associations between diabetes and pancreatic cancer have been reported in epidemiologic studies. Further, the biologic perturbations that lead to these two diseases occur in several of the same cell types in the pancreas, and may involve common metabolic pathways. Thus, it is reasonable to postulate that genes known to be associated with diabetes may also predispose to pancreatic cancer, although no study to date has addressed this hypothesis. We propose to investigate associations of single nucleotide polymorphisms (SNPs) and haplotypes in six diabetes candidate genes with risk for pancreatic cancer. We will use a nested case-control design based on 85 incident cases of pancreatic cancer and 170 matched controls originally recruited into the (3-Carotene and Retinol Efficacy Trial (CARET), all of whom were smokers. This study design avoids bias to due case fatality, and potential confounding effects due to smoking. Biospecimens for obtaining DNA are available for all participants, as is relevant clinical data. Thus, the CARET cohort is uniquely suited for this project. Genotyping will be performed at the Functional Genomics Laboratory at the University of Washington. Haplotypes will be constructed using recently developed software, and both univariate and multivariate statistical approaches will be used to assess genetic associations. The pilot study proposed in this application is appropriate for the """"""""Exploratory Studies in Cancer Detection, Diagnosis, and Prognosis"""""""" program announcement because it tests a new, exploratory hypothesis: whether or not candidate genes for diabetes may be molecular biomarkers for risk of pancreatic cancer, based on a sound scientific rationale. The proposed study is innovative because it combines existing resources and technologies in novel ways. It is significant because understanding common genetic susceptibility factors for diabetes and pancreatic cancer may lead to an identification of genetic biomarkers that could be used to better predict pancreatic cancer. The results may facilitate translational studies of early detection and prevention of pancreatic cancer, especially among patients diagnosed with diabetes. ? ?
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