Colorectal carcinogenesis is a multistep process, with the adenoma as the usual intermediate step in development of most colorectal cancers (CRC), but the vast majority of adenomas have little risk of progression or malignancy. It is of great clinical importance to identify and characterize the subset of adenomas that are likely to progress, and furthermore to identify the molecular, dietary and lifestyle factors that contribute to their pathogenesis as the basis tor prevention. Loss of imprinting of the insulin-like growth factor 2 (IGF2) gene is associated with increased risk of CRC. In addition, serrated adenomas have drawn recent attention as a precursor to CRC. Neither loss of imprinting nor serrated adenomas have been studied extensively. We will test three novel hypotheses. First, that a group of individuals is specifically predisposed to developing advanced colorectal pre-neoplastic lesions, a phenotype that is clinically definable by an advanced adenoma. We will identify and establish the molecular features of this "high risk colorectal adenoma phenotype" by characterizing mutations in K-ras or BRAF genes and methylation of CpG islands in genes and markers in advanced adenomas compared to non-advanced adenomas in the three large phase III prevention trials and in the National Cancer Institute's Polyp Prevention Trial. We will also determine loss of imprinting of IGF2 in peripheral blood leukocytes of subjects with the high risk colorectal adenoma phenotype compared with subjects who lack advanced colorectal adenomas. Secondly, we hypothesize that the serrated adenoma constitutes a specific and clinically important subset of the high risk colorectal adenoma phenotype. We will address criteria for categorization of serrated adenomas and their molecular features (K-ras and BRAF mutation, methylation, microsatellite instability,proliferation, apoptosis, and expression of mismatch repair gene products in tissue microarrays) compared to non-serrated adenomas. We will also determine the association of serrated histopathology to clinical and other pathologic characteristics and to recurrence to establish if a serrated adenoma defines the high risk olorectal adenoma phenotype. Thirdly, we hypothesize that the high risk colorectal adenoma phenotype and serrated adenomas are associated with specific dietary and lifestyle factors, and we will analyze these in concert.In a secondary aim, we will evaluate the effects of chemoprevention interventions on the high risk colorectal adenoma phenotype and serrated adenomas in the intervention groups of the Celecoxib/Selenium. Identification of the pathologic, molecular, lifestyle, and dietary factors that characterize individuals who develop high risk adenomas will provide valuable information for development of CRC prevention strategies and an in-depth understanding of mportant precursor lesions.