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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Kagan, Jacob
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University of Washington
Schools of Medicine
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Salk, Jesse J; Bansal, Aasthaa; Lai, Lisa A et al. (2013) Clonal expansions and short telomeres are associated with neoplasia in early-onset, but not late-onset, ulcerative colitis. Inflamm Bowel Dis 19:2593-602
Ussakli, Cigdem Himmetoglu; Ebaee, Anoosheh; Binkley, Jennifer et al. (2013) Mitochondria and tumor progression in ulcerative colitis. J Natl Cancer Inst 105:1239-48
Zisman, Timothy L; Bronner, Mary P; Rulyak, Stephen et al. (2012) Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines. Inflamm Bowel Dis 18:2240-6
Lai, Lisa A; Risques, Rosa Ana; Bronner, Mary P et al. (2012) Pan-colonic field defects are detected by CGH in the colons of UC patients with dysplasia/cancer. Cancer Lett 320:180-8
Risques, Rosa Ana; Lai, Lisa A; Himmetoglu, Cigdem et al. (2011) Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation. Cancer Res 71:1669-79
May, Damon; Pan, Sheng; Crispin, David A et al. (2011) Investigating neoplastic progression of ulcerative colitis with label-free comparative proteomics. J Proteome Res 10:200-9
Bronner, Mary P; Skacel, Marek; Crispin, David A et al. (2010) Array-based comparative genomic hybridization in ulcerative colitis neoplasia: single non-dysplastic biopsies distinguish progressors from non-progressors. Mod Pathol 23:1624-33
Salk, Jesse J; Salipante, Stephen J; Risques, Rosa Ana et al. (2009) Clonal expansions in ulcerative colitis identify patients with neoplasia. Proc Natl Acad Sci U S A 106:20871-6
Brentnall, Teresa A; Pan, Sheng; Bronner, Mary P et al. (2009) Proteins That Underlie Neoplastic Progression of Ulcerative Colitis. Proteomics Clin Appl 3:1326
Risques, Rosa Ana; Lai, Lisa A; Brentnall, Teresa A et al. (2008) Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. Gastroenterology 135:410-8

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