P072. Ezrin, LAMC2 and ITG α 6 as possible biomarkers of ulcerative colitis-associated colonic dysplasia
J. Bjerrum1, J. Olsen2, G. Rogler3, O. Nielsen1, 1Herlev Hospital, Department of Gastroenterology, Medical Section, Herlev, Denmark, 2Panum, Copenhagen University, Department of Cellular and Molecular Medicine, Copenhagen, Denmark, 3University Hospital Zürich, Division of Gastroenterology and Hepatology, Zürich, Switzerland
Patients with extensive ulcerative colitis (UC), a longer duration of disease, concomitant primary sclerosing cholangitis, or a family history of colorectal cancer (CRC) have an increased risk of dysplasia and ultimately CRC. Early detection of dysplasia is crucial in terms of timely and effective treatment. This study used DNA microarray-based gene expression profiles from colonic pinch biopsies of patients with UC and UC-associated dysplasia to identify distinct molecular signatures and biomarkers for dysplastic transformation.
Mucosal pinch biopsies were obtained from the descending colon of forty-seven patients with active (i.e. a Mayo score ≥2) UC. Thus, the study included 7 UC-associated dysplasia, 20 pancolitis, 20 left-sided colitis, and 15 controls. Genome-wide gene expression analyses were performed using Affymetrix GeneChip Human Genome U133 Plus 2.0. Real time RT-PCR and immunohistochemistry were applied to validate selected microarray data. The microarray data were analyzed by principal component analysis, Hotelling T2 tests, and overrepresentation analysis for Gene Ontology terms. The RT-PCR data were analyzed with the Wilcoxons' rank sum test.
Based on the microarray data the four groups were found molecular distinct, and the annotation analysis suggested that transcripts involved in membrane-associated components were deregulated in dysplasia. Based on these findings and their known involvement in neoplasia, ezrin, laminin γ 2 (LAMC2), and integrin α 6 (ITG α 6) were selected for further validation in terms of RT-PCR and immunohistochemistry. As suggested by the microarray data the RT-PCR studies found ezrin, LAMC2, and ITG α 6 to be significantly (p < 0.05) decreased in dysplastic samples compared to pancolitis, left-sided colitis, and controls. The microarray and RT-PCR results are currently being validated with immunohistochemistry.
The gene expression profiles of the colonic mucosa from patients with UC-associated dysplasia, pancolitis, left-sided colitis, and controls are distinct, and the transcripts of the membrane-associated components ezrin, LAMC2, and ITG α 6 are significantly down-regulated in dysplasia compared to the three other groups. As ezrin, LAMC2, and ITG α 6 are persistently found up-regulated in carcinomas, their decreased expression in dysplasia seems to distinguish this premalignant state. Consequently, ezrin, LAMC2, and ITG α 6 might be excellent biomarkers of UC-associated dysplasia.