Cytochrome C Oxidase-I Deficient Foci in Ulcerative Colitis: A Novel Surrogate Biomarker of Early Carcinogenesis
HS McElligott, J Liao, MS Rao, GY Yang. Northwestern University, Chicago, IL
Background: Oxidative stress has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and its progression to colorectal carcinoma. Cytochrome oxidase c subunit I (CcOI) is a key mitochondrial enzyme involved in apoptosis regulation. Experimental data show extensive positive expression of CcOI in normal tissues with loss of expression associated with its gene mutation and mutant cells displaying a clonal growth pattern. Thus, CcOI may be a unique biomarker for assessing oxidative stress-induced gene mutations, clonal cell growth, and carcinogenesis. Our study explored the potential of CcOI as an early biomarker of IBD-associated carcinogenesis by comparing CcOI expression patterns in ulcerative colitis (UC) to normal colon.
Design: 70 colectomy specimens from patients with varying degrees of involvement by UC, and 5 segmental resections for diverticulosis of normal colon were examined for CcOI expression patterns. Immunohistochemistry was performed for CcOI on each case. Normal colon served as a positive control.
Results: In normal colon, extensive positive staining for CcOI was seen in epithelial and stromal cells. Rare single glands showed loss of CcOI expression (Fig A). CcOI-deficient foci were defined as consecutive glands showing 50% staining loss mainly in the crypts and were categorized as either macrofoci (5 glands) (Fig B) or microfoci (<5 glands) (Fig A). CcOI-deficient foci were quantitated as number of foci per 100 glands. In normal colon, no macrofoci and only occasional microfoci were identified; greater than 95% of foci were single glands only. In UC specimens both macro and microfoci of CcOI loss were identified. The mean number of macrofoci/100 glands was 0.45+/-0.5, and the mean number of microfoci/100 glands was 0.3+/-0.8, significantly less than in control colon. 8 cases of UC (11%) showed extensive (>50%) loss of CcOI expression (Fig C).
Conclusions: Our results indicate that CcOI-deficient foci may serve as a useful surrogate biomarker of early carcinogenesis in patients with inflammatory bowel disease, particularly for early disease detection and prevention in this patient population. It also warrants investigating the biologic events in these foci in future.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 100, Monday Morning