This Cancer Prevention, Control, and Population Sciences Career Development Award will provide Dr. Shrubsole and her mentors a detailed strategy for Dr. Shrubsole to achieve independence as a cancer researcher, particularly colorectal cancer. New knowledge and skills in colorectal cancer biology, epigenetics, and molecular/genetic epidemiology methods will be obtained in the training plan of the award including through coursework, seminars, national meetings, and regular meetings with mentors. These skills will be translated to research examining lifestyle, genetic and epigenetic susceptibility, and colorectal adenoma risk. Folate, a B vitamin is essential for regenerating methionine, the methyl donor for DMA methylation. Evidence of a role of low folate and/or methionine in colorectal adenoma/cancer risk is accumulating. Simultaneously, there is increasing evidence that aberrant DNA methylation, such as hypermethylation of tumor suppressor genes, is increased in both colorectal cancers and adenomas. To advance our understanding of the role of diet and DNA methylation in adenoma development, epidemiologic studies examining the role of these factors and genes involved in DNA methylation associated pathways are needed. Thus, the research goals of this proposal are to evaluate in a large colorectal adenoma case-control study (n=3000) risk associated with methyl-group intake (folate, methionine, vitamin B6, vitamin B12), polymorphisms in genes involved in methyl-group transfer (MTHFR, DNMT1, DNMT3A), promoter methylation of tumor suppressor genes in normal rectal mucosa (APC, RASSF1 A, n=4DO), and the combined association of these factors. The methylation phenotype in normal rectal mucosa will be compared with methylation phenotype in adenomas. Additionally, the potential utility of methylation phenotype in normal rectal mucosa as a marker of adenoma risk will be evaluated by studying factors that affect level of methylation. Primary research support will come from an existing molecular epidemiology study of the candidate's primary mentor, Dr. Wei Zheng. This work will extend our understanding of links between DNA methylation and adenoma risk as well as interactions with genetic susceptibility. It may also serve to help identify high-risk populations for colorectal adenoma. The research work in this CDA will serve as the basis for submission of competitive R01 proposals by the candidate in latter years of this award.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07CA122451-04
Application #
7851193
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$131,058
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Su, Timothy; Washington, M Kay; Ness, Reid M et al. (2017) Comparison of biomarker expression between proximal and distal colorectal adenomas: The Tennessee-Indiana Adenoma Recurrence Study. Mol Carcinog 56:761-773
Davenport, James R; Cai, Qiuyin; Ness, Reid M et al. (2016) Evaluation of pro-inflammatory markers plasma C-reactive protein and urinary prostaglandin-E2 metabolite in colorectal adenoma risk. Mol Carcinog 55:1251-61
Coleman, Helen G; Loughrey, Maurice B; Murray, Liam J et al. (2015) Colorectal Cancer Risk Following Adenoma Removal: A Large Prospective Population-Based Cohort Study. Cancer Epidemiol Biomarkers Prev 24:1373-80
Coleman, Helen G; Ness, Reid M; Smalley, Walter E et al. (2015) Aspects of dietary carbohydrate intake are not related to risk of colorectal polyps in the Tennessee Colorectal Polyp Study. Cancer Causes Control 26:1197-202
Shrubsole, Martha J; Wagner, Conrad; Zhu, Xiangzhu et al. (2015) Associations between S-adenosylmethionine, S-adenosylhomocysteine, and colorectal adenoma risk are modified by sex. Am J Cancer Res 5:458-65
Kweon, Sun-Seog; Shu, Xiao-Ou; Xiang, Yongbing et al. (2014) One-carbon metabolism dietary factors and distal gastric cancer risk in chinese women. Cancer Epidemiol Biomarkers Prev 23:1374-82
Luo, Yanxin; Wong, Chao-Jen; Kaz, Andrew M et al. (2014) Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. Gastroenterology 147:418-29.e8
Shrubsole, Martha J; Cai, Qiuyin; Wen, Wanqing et al. (2012) Urinary prostaglandin E2 metabolite and risk for colorectal adenoma. Cancer Prev Res (Phila) 5:336-42
Shrubsole, Martha J; Shu, Xiao Ou; Li, Hong-Lan et al. (2011) Dietary B vitamin and methionine intakes and breast cancer risk among Chinese women. Am J Epidemiol 173:1171-82