Our overall objective is to better define the role DNA methylation in the etiology of colorectal adenomas, and to assess potential risk factors for de novo methylation in adenomas. We propose to accomplish our objective by adding a methylation component onto an existing sigmoidoscopy-based case-control study of environmental and genetic risk factors for adenomatous polyps of the large bowel that will have 1,000 cases and 1,000 controls, with food frequency and risk factors questionnaires, a fasting blood sample, and, for cases, pathology reports and tumor blocks. We propose the following aims: First, we will conduct a descriptive study of de novo methylation in five specific genes, three known tumor suppressor genes (APC, hMLH1, and p16) involved in colorectal of hypermethylation of the promoter region cancer, the estrogen receptor (ER), which may or may not be directly involved in the etiology of colorectal polyps, and a """"""""control"""""""" gene, MYOD, that is clearly not involved in colorectal cancer. Second, we will assess two hypotheses regarding risk factors for hypermethylation. The first is that decreased dietary or RBC folic acid will be associated with an increase prevalence of hypermethylation of the promoter region of the ER. As part of this hypothesis, we will assess modification of the folic acid-methylation relationship by a gene, methylene-tetrahydrofolate reductase (MTHFR), that is involved in folic acid metabolism. The second hypothesis is that use of postmenopausal hormones will be associated with a lower prevalence of hypermethylation of the ER. Third, we will determine if there are differences in the methylation status of the five target genes in adenomas with the replication error phenotype (RER+) compared to adenomas without that phenotype (RER-). We propose to measure methylation status with a new procedure (COBRA), developed by Dr. Peter Laird , that more sensitive and quantitative than other assays that can feasibly be conducted on a large sampled of paraffin-embedded tissue. Combining this assay with our ongoing study will provide us with a powerful means of addressing important questions about methylation and its role on cancer. We propose to measure methylation status with a new procedure (COBRA), developed by Dr. Peter Laird, that is more sensitive and quantitative than other assay with our ongoing study will provide a powerful means of addressing important questions about methylation and its role on cancer etiology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077376-04
Application #
6626599
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Patel, Appasaheb1 R
Project Start
2000-01-20
Project End
2004-12-31
Budget Start
2003-01-23
Budget End
2004-12-31
Support Year
4
Fiscal Year
2003
Total Cost
$566,943
Indirect Cost
Name
University of Southern California
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089