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.
