CpG Island Methylator Phenotype in Human Colorectal Cancer

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DESCRIPTION (provided by applicant): Human colorectal cancer arises as a consequence of both genetic and epigenetic alterations, including promoter CpG island hypermethylation. A subset of colorectal tumors has been described to have an unusually high number of hypermethylated CpG islands, leading to the definition of a distinct phenotype, referred to as "CpG Island Methylator Phenotype", or "CIMP". The long-term objective of this proposal is to study the association between CIMP status and molecular, demographic, and histopathologic features, and environmental risk factors, using colorectal cancer samples collected through the Cooperative Family Registry for Colorectal Cancer Studies (Colon CFR), an NCI-supported consortium intended as a resource to promote collaborative and interdisciplinary studies in the genetic epidemiology of colorectal cancer. We have recently published an improved DMA methylation marker set and analysis technology with which CIMP can be efficiently defined with high accuracy in archival colorectal cancer specimens. We propose to 1) estimate the association between CIMP status and age, sex, family history, race and country of origin, using 4,943 population-based colorectal cancer samples collected through the Colon CFR, 2) estimate the association between CIMP status and tumor location, grade, invasive margin, lymphocytic infiltration, direct spread, lymph node spread, venous spread and type of residual adjacent polyp, if present, and 3) estimate the association between CIMP status and selected risk factors, both genetic and environmental/lifestyle factors, including somatic mutations in BRAF, germline mutations in the MMR genes, smoking history, red meat and alcohol intakes, dietary folate intake, folate metabolic enzyme polymorphisms and history of hormone use. This study will contribute to our understanding of the etiology of CIMP, and its relationship to other molecular and histopathologic features of colorectal cancer. Colorectal cancer involves changes to genes that control cell growth and division. These changes can be structural, as in the case of genetic mutations, or they can reflect an alteration in how actively the gene is being used, referred to as an epigenetic change. This study will investigate how some colorectal tumors acquire an unusually high number of epigenetic changes, with the long-term goal of using this knowledge to block or reverse these types of deleterious changes.