Abstract Colon cancer is the second most common cancer in men and women in the United States. The average lifetime risk for developing colon cancer is about 7%. This lifetime risk is increased several fold in individuals with an inflammatory bowel disease, and increases further with greater extent, duration and severity of inflammation. The role of inflammation in many cancers is becoming clearer, but the mechanism(s) by which inflammation may initiate or support cancer growth remains to be elucidated. Our laboratory has developed a rodent model of colon cancer, the Polyposis in rat colon (Pirc) rat, which closely mimics the predisposition for colonic neoplasia observed in humans. Colonic inflammation in the Pirc rat induced by dextran sodium sulfate (DSS) increases the number of colon tumors up to ten-fold, and include invasive adenocarcinomas as early as five months of age. To ascertain molecular differences between colonic tumors and normal colonic epithelium in DSS-treated Pirc rats, and colonic tumors and normal colonic epithelium in untreated Pirc rats, tissues were harvested at 97 days of age, before any detectable difference in tumor invasion. Agilent Whole Rat Genome expression microarrays were run on several biological replicates of each sample type. As expected, many genes (4630) were differentially expressed between normal epithelium and colonic tumors (>2-fold change, 0.05 FDR). Surprisingly, no significant difference in gene expression was observed between tumors from untreated and DSS-treated Pirc rats. However, over 950 genes showed differential expression in normal epithelium between untreated and DSS-treated Pirc rats. Further, many of the genes in apparently normal epithelial tissue from DSS-treated Pirc rats showed an expression profile intermediate between normal untreated Pirc epithelium and tumors. Several of these candidates have been confirmed by qRT-PCR. DSS-treated animals eventually develop a large number of tumors throughout the colon. This expression profile could indicate that this apparently normal tissue contains nascent tumors. Alternatively, this could represent changes in the normal tissue surrounding the tumor that supports the growth and invasion of colonic neoplasms. This distinction requires further investigation using other biological endpoints. Wild type rats treated with DSS develop a “cobblestone” pattern in the colon, but rarely form even a single tumor. Microarray profiling of normal epithelium from untreated and DSS-treated wild type rats may reveal whether the signatures we have seen in the apparently normal colonic epithelium from DSS-treated Pirc rats is simply an undetected tumor. Using endoscopy we can longitudinally obtain biopsy samples to see whether these expression profiles change over time from normal epithelium to an invasive cancer. Comparing our data to that in humans with ulcerative colitis will help focus future exploration of candidate genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4279. doi:1538-7445.AM2012-4279