See instoictions): Ulcerative colitis (UC), a chronic inflammatory disease ofthe colon, affects half a million individuals in the USA and predisposes them to develop colorectal cancer. The current method of cancer prevention consists on life-long endoscopic surveillance every 1-3 years. Colonoscopies are expensive, time consuming, invasive, and do not always detect dysplasia. Thus, better methods are needed to detect the presence of dysplasia and cancer and to predict the patients at risk (estimated to be 10%). Senescence biomarkers are promising candidates because they have been found overexpressed in pre-neoplastic tissues and also because senescence is induced by telomere shortening, oxidative stress and DNA damage, three stimuli that play a role in ulcerative colitis'tumorigenesis. Thus, we hypothesize that senescence is likely to be increased in histologically normal tissue from UC patients with coexistance or at risk of progression to HGD or cancer. The main goal of this proposal is to improve colorectal cancer prevention in UC by using senescence biomarkers to (1) accurately distinguish UC progressors (patients with high-grade dysplasia or cancer) from UC non progressors, and (2) predict which patients dysplasia-free at endoscopy are at high risk of developing high-grade dysplasia or cancer. First, we will develop a panel of senescence markers that can be detected by Immunohistochemistry in formalin-fixed paraffin embedded colon tissue. This is a very standard technique that will facilite the clinical application of these biomarkers if their value in cancer prevention is proved. Then, we will select the combination of parameters (number of markers, level of expression, number of biopsies) that define the "progressor signature" for UC patients and we will analyze the ability of this signature to discriminate beween UC progressors and non-progressors, first in a training set and then in a validation set. Finally, we will determine the ability of the progressor signature and additional combinations of senescence biomarkers to predict the risk of progression to dysplasia or cancer using a large, prospectively collected cohort of ulcerative colitis patients.

Public Health Relevance

Ulcerative colitis, a chronic inflammatory disease ofthe colon, affects half a million individuals in the USA and predisposes them to develop colorectal cancer. This proposal aims to improve cancer prevention in this disease by using senescence biomarkers easily measured in routinely collected colon biopsies. These markers will help to predict who are the patients that will develop colorectal cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Academic/Teacher Award (ATA) (K07)
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Subcommittee G - Education (NCI)
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Perkins, Susan N
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University of Washington
Schools of Medicine
United States
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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
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
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