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 earlier, more cost effective diagnosis of curable cancer or its precursors in these patients.
Specific Aim 1. To determine the molecular genetic abnormalities in early colonic tumorigenesis in ulcerative colitis and to develop simplified techniques for detecting them.
Specific Aim 2. To develop a panel of early genetic markers that best predicts the future development of dysplasia and cancer and to test these markers prospectively by colonoscopic biopsy surveillance.
In Specific Aim 1 the earliest indicators of future progression to dysplasia and cancer will be sought primarily in colectomy specimens by comparing mutations and/or allelic losses in various tumor suppressor genes (initially p53 (17p), APC (5pq) and 8p (telomeric), mismatch repair genes MSH2 and MutL, and then DDC (19q), Rb (13q) & MCC (5q)) with other with other variables such as DNA ploidy and histology. Rapid molecular genetic screening assays for these genetic defects will be developed and tested in material collected at colonoscopy as part of Specific Aim 2. The most reliable markers for the early prediction of future neoplastic progression will be determined. The preliminary data indicate that DNA aneuploidy predicts future progression to dysplasia or cancer in patients whose colonic mucosal biopsies are histologically negative or indefinite for dysplasia. Because the pilot studies show that p53 mutations may occur before the development of DNA aneuploidy, they will determine whether p53's presence is an earlier marker of cancer risk than aneuploidy. The preliminary work with the MSH2 gene suggests that a germline mutation, detectable by peripheral blood assay, identifies a subset of UC patients at high risk for neoplastic progression. They will evaluate the value of MSH2 as a marker of risk in prospective follow up. The proposed studies will ultimately achieve an enhanced understanding of neoplastic progression in the UC model, improve and reduce the costs of the management of these patients, and reduce their risk of death from cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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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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