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Project 4: Genetic and Epigenetic Markers for Colorectal Adenoma Recurrence

Most colorectal cancers (CRCs) arise from adenomatous polyps, and a large proportion of adenoma patients develop new (metachronous) adenomas after their initial polypectomy. There is considerable controversy regarding an appropriate surveillance interval for adenoma patients after removal of their initial adenomas. Given the cost and risks of colonoscopies, these procedures should be done only among those at a high risk of adenoma recurrence. Therefore, studies assessing predictors for recurrent adenomas, particularly among patients with multiple or pathologically advanced adenoma(s), will provide valuable information to stratify patients into low- to high-risk groups for cost-effective surveillance and chemoprevention strategies. Some tumor markers (genetic or epigenetic alterations) involved in the formation of colorectal neoplasia may be promising predictors for recurrent adenomas, as they are believed to reflect a field cancerization process of colorectal tumors. We hypothesize that patients whose initial adenomas have certain altered genetic or epigenetic profiles may have an elevated risk of adenoma recurrence, and these tumor markers can be used to predict the risk of adenoma recurrence. As part of The Cancer Genome Atlas (TCGA) project, a large number of samples from CRC patients are being analyzed to catalog molecular aberrations that cause CRC. These data will enable us to expand the search of tumor markers in relation to adenoma recurrence.

Since 2007, nearly 20 genetic susceptibility loci for CRC have been identified in genome-wide association studies (GWAS). Although each of these common risk variants confers a small to moderate risk for CRC, the cumulative effect of these variants combined could be substantial. Since these GWAS-identified risk variants reflect individual genetic predisposition to CRC, and individuals with a high risk of adenoma recurrence are believed to be at a particularly high risk of developing CRC, we hypothesize that risk variants for CRC also may be associated with adenoma recurrence, and these genetic risk variants could be used, along with other markers, to predict adenoma recurrence.

To test these hypotheses, we propose to conduct a follow-up study in approximately 1,500 patients diagnosed with either multiple adenomas or a pathologically advanced adenoma. These patients have already been recruited in our previous studies conducted in Tennessee and Indiana. In addition to clinical and epidemiologic data, we have already obtained genomic DNA samples, fresh-frozen polyp tissues and formalin-fixed, paraffinembedded (FFPE) from approximately 80%, 30% and 50% of these patients, respectively. These biological samples will be available for the proposed study.

Aim 1: To follow-up study participants to collect information related to follow-up exams and adenoma recurrence and to obtain FFPE blocks of initial adenomas from remaining patients whose samples have not yet been collected.

Aim 2: To evaluate the association of adenoma recurrence with genetic and epigenetic tumor markers. 

Aim 3: To investigate the association of adenoma recurrence with all GWAS-identified genetic variants using germline DNA samples collected in the study.

Aim 4: To establish a risk-assessment model and evaluate the utility of genetic and tumor markers alone and in combination with known predictors (such as pathologic features of initial adenomas) in predicting the risk of adenoma recurrence.