Frequent Loss of Heterozygosity of a DNA Repair Gene, hOGG1, in Inflammatory Bowel Disease
DC Phan, CM Quick, H Zhang, L Gilbrech, SA Schichman, BR Smoller, LW Lamps, C-Y Fan. University of Arkansas for Medical Sciences, Little Rock, AR; John L. McClellan Memorial Veterans Hospital, Little Rock, AR
Background: Inflammatory bowel disease of the colon is an inflammatory process with a documented risk of epithelial dysplasia and development of adenocarcinoma. The hallmark of inflammatory bowel disease is persistent chronic active colitis, in which the recuited inflammatory cells can produce reactive oxygen species, generating a state of oxidative stress and frequently oxidative damage in DNA. Among various oxidative DNA lesions, 8-oxoguanine is by far the most abundant and mutagenic, if not sufficiently repaired. The gene encoding human 8-oxoguanine DNA glycosylase 1 (hOGG1), capable of excision repair of 8-oxoguanine, showed frequent gene loss or loss of heterozygosity (LOH) in a variety of human malignant neoplasms, such as head and neck squamous cell carcinoma and renal cell carcinoma. However, no study has been done to illustrate whether or not this gene will be altered in the course of inflammatory bowel disease.
Design: A total of 12 cases with established diagnosis of inflammatory bowel disease were included in the study. Twelve pairs of inflamed and adjacent normal colonic mucosa were used for microdissection of tissue. DNA samples were then obtained from dissected tissue sections. These DNA samples (24) were subjected to PCR amplification using 4 fluorescent-labeled microsatellite makers (D3S1289, D3S1297, D3S1300 and D3S1274), followed by fragment analysis using ABI PRISM 3100 Genetic Analyzer.
Results: All 12 cases are informative with at least one of 4 microsatellite makers used. Among these 12 cases, 7 (58.3%) cases showed evidence of LOH in at least one of the 4 markers used and the remaining 5 (41.7%) displayed retention of heterozygosity (RH) at the hOGG1 gene locus.
Conclusions: Loss of heterozygosity (gene loss) of the hOGG1 gene frequently occurs in inflamed colonic mucosa (58.3%) in inflammatory bowel disease. Thus, the combination of oxidative stress commonly associated with inflammatory conditions and defects in repair gene involved in oxidative DNA damage may be one important molecular mechanism by which colonic epithelium undergoes in the malignant transformation which is frequently observed in inflammatory bowel disease.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 105, Monday Morning