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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118699-05
Application #
8101206
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Nelson, Stefanie A
Project Start
2007-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$494,429
Indirect Cost
Name
University of Southern California
Department
Surgery
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Hua, Xinwei; Phipps, Amanda I; Burnett-Hartman, Andrea N et al. (2017) Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival. J Clin Oncol 35:2806-2813
Levine, A Joan; Phipps, Amanda I; Baron, John A et al. (2016) Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors. Cancer Epidemiol Biomarkers Prev 25:68-75
Weisenberger, Daniel J; Levine, A Joan; Long, Tiffany I et al. (2015) Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history. Cancer Epidemiol Biomarkers Prev 24:512-519
Phipps, Amanda I; Limburg, Paul J; Baron, John A et al. (2015) Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology 148:77-87.e2
Levine, A Joan; Win, Aung Ko; Buchanan, Daniel D et al. (2012) Cancer risks for the relatives of colorectal cancer cases with a methylated MLH1 promoter region: data from the Colorectal Cancer Family Registry. Cancer Prev Res (Phila) 5:328-35
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Berman, Benjamin P; Weisenberger, Daniel J; Aman, Joseph F et al. (2011) Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet 44:40-6
Protiva, Petr; Mason, Joel B; Liu, Zhenhua et al. (2011) Altered folate availability modifies the molecular environment of the human colorectum: implications for colorectal carcinogenesis. Cancer Prev Res (Phila) 4:530-43

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