HISTOLOGIC AND MOLECULAR CHANGES IN UC TUMORIGENESIS

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The long term objectives of this research are to develop a better understanding of the molecular mechanisms of neoplastic progression in chronic extensive ulcerative colitis (UC) and to use this knowledge for the prevention of cancer in UC. Our previous studies have indicated that chromosomal instability (CIN), detected by the presence of DNA aneuploidy, is a risk factor for the histologic progression to dysplasia or cancer. Recently, we have found that fluorescence in situ hybridization (FISH) is a more sensitive indicator of CIN: this method is able to detect evidence of chromosomal instability throughout the colon of patients with focal dysplasia or cancer. We believe that CIN is a reflection of the underlying process that contributes to cancer risk in UC. In our specific aim 1, we will determine the causes and patterns of CIN in UC, testing the hypotheses that it is related to elevated DNA damage or shortening of telomeres. In specific aim 2, we will determine whether dietary interventions can influence the levels of CIN as determined by markers derived from specific aim 1. Specifically, we propose two double-blind, placebo controlled, prospective pilot intervention studies: 1) using folate in UC patients with indefinite histology for dysplasia and 2) using ursodeoxycholic acid in UC patients with low-grade dysplasia in their colons. We will test for chromosomal instability pre and post intervention. If our hypothesis that CIN can be exploited as an early marker of dysplasia is correct, it might enable clinicians to take a few rectal biopsies, determine those patients who are at greatest risk for neoplastic progression and concentrate colonoscopic surveillance efforts on them. Moreover, this knowledge could help provide the underpinnings for development of cancer prevention strategies.