Colorectal cancer is one of the most feared complications of ulcerative colitis (UC), an inflammatory bowel disease that affects more than half a million individuals in the United States. To reduce cancer morbidity and mortality, patients with UC undergo colonoscopies every 1-2 years to monitor precancerous dysplasia. Tumorigenesis in UC is a multistep process that involves progression through low-grade dysplasia (LGD), high-grade dysplasia (HGD), and cancer. Because dysplasia in UC is often flat and difficult to detect, 4-quadrant biopsies from every 10cm of colon are taken at colonoscopy to be histologically evaluated. Patients with HGD or cancer undergo colectomy. Patients with LGD undergo colectomy, if multifocal, or repeated colonoscopies every 3-6 months, if unifocal. This intensive surveillance protocol is time-consuming, expensive, and of limited sensitivity to find dysplasia. The limitations of this system are aggravated by the fact that the prevalence of UC is increasing, but the risk of cancer progression in UC is decreasing. Thus, it is more crucial than ever to find biomarkers to detect who are the patients at high risk of cancer, so that clinical resources can be directed to them, while reducing anxiety and colonoscopies for the majority of patients without increased cancer risk. We have previously demonstrated that the patients at risk of cancer can be identified by analyzing molecular alterations that are present in large, non-dysplastic fields that surround dysplastic foci and often expand to involve the whole colon. Previous biomarkers, however, failed to reach the clinic because they were based on techniques that rely on frozen biopsies, which are not available in large numbers to perform the necessary validations studies. In this proposal, we present strong preliminary data that demonstrates that mitochondrial alterations occur in large, non-dysplastic fields that precede dysplasia, and can be detected in formalin-fixed, paraffin-embedded (FFPE) biopsies by immunohistochemistry and Nanostring, a novel technology that allows digital counting of mRNA expression. Our goal is to develop mitochondrial biomarkers based on these two techniques according to the EDRN phases for biomarker development. Phase I consists on the training of the biomarker and it will be performed for mitochondrial proteins by immunohistochemistry in Aim 1 and for mitochondrial gene expression by Nanostring in Aim 2. The biomarkers will be designed to detect the presence of HGD or cancer elsewhere in the colon by analyzing only 3-6 random colon biopsies from UC patients with HGD or cancer (Progressors) and UC patients dysplasia-free (Non Progressors).
In Aim 3, we will validate the biomarkers in an independent set of patients.
In Aim 4 we will test the ability of the biomarkers to predict progression to cancr in patients with non-dysplastic or LGD biopsies. These studies are likely to produce a useful and much needed biomarker of cancer risk in UC, which could be replicated by other groups using archival FFPE material in order to complete its validation and quick translation to the clinic.

Public Health Relevance

Colorectal cancer is a feared long-term complication of ulcerative colitis, an inflammatory bowel disease that affects more than half a million individuals in the United States. Although these patients undergo colonoscopies every 1-2 years, the detection of pre-cancerous lesions is challenging. This research will improve detection of pre-cancerous lesions in ulcerative colitis by analyzing mitochondria, the organelles in charge of energy production in cells. It is well know that mitochondrial alterations contribute to tumor progression and we propose to detect these alterations with two highly translational techniques. Biomarkers developed here could facilitate early cancer detection in ulcerative colitis and, potentially, in other cancers of inflammatory origin.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Vydelingum, Nadarajen A
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University of Washington
Schools of Medicine
United States
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