According to current clinical practice guidelines, hyperplastic polyps are benign lesions that can be safely ignored. However, recent evidence suggests that hyperplastic polyps, a common finding in nearly 30% of adults, may indeed be pre-neoplastic lesions. While only a minority of hyperplastic polyps progress to malignancy, the characteristics of those at-risk lesions are not fully known. In molecular terms, the presence of microsatellite instability (MSI) and/or CpG island methylation (CIMP) may be the hallmark of hyperplastic polyps that give rise to sporadic colorectal carcinomas. In this emerging paradigm, there is a great need to confirm these findings on a well-characterized sample, and more importantly, to understand the environmental and genetic characteristics that are associated with hyperplastic polyps, particularly in comparison to the better understood adenomas. To investigate the relationship between risk factors, epigenetic characteristics, and polyps, we propose to conduct a population based case-control study of hyperplastic polyps, adenomatous polyps, and normal controls. Individuals with a new diagnosis of polyps (hyperplastic polyps n=700, adenomas n=700) will be identified by a centralized review of the pathology files of Group Health Cooperative (GHC) of Puget Sound a large health maintenance organization. Similarly aged individuals with normal screening colonoscopies (n=700) will be identified from procedure files. All subjects will complete a standardized interview and provide a buccal sample. The diagnostic materials of all cases will be reviewed, DNA extracted from lesional blocks, and MSI and CIMP status will be assessed using standard panels of markers. Polymorphisms in epoxide hydrolase (mEH), which are involved in the detoxification of polyaromatic hydrocarbons in smoke and cooked meat, will be evaluated for their modifying effect on environmental exposures. This study will provide the largest study of risk factors for hyperplastic polyps, their genetic characterization, and comparisons to adenomas and normals. In this study neoplastic pathways will be classified on the basis of genetic instability, DNA methylation phenotype, and epidemiologic risk factors. The results of this study will have implications for understanding the biology and prevention of colorectal cancer.
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