Colorectal cancer (CRC) is third most common malignancies worldwide and the mechanism of tumorigenesis is unknown. The goal of this study is to understand the role of chronic inflammation and DNA damage in tumorigenesis and tumor progress in the colon. Analyses of ulcerative colitis (UC)-associated CRC samples revealed that tumorigenesis is involved in infiltrating of leukocytes, increased DNA damage, telomere shortening, and senescence. Interestingly, we have recently discovered a unique mouse model that spontaneously develops chronic inflammation in the colon, dysplasia and adenocarcinoma, recapitulating the pathogenic features of UC-associated CRC. We propose to assemble a collaborative team to study the animal models and to analyze human colon samples in parallel. The main hypothesis is immune deregulation results in inflammation to the commensal microbial in the guts, which leads in increased ROS and secretion of cytokines, providing a key environment for cancer formation and progression. With the environment, DNA damage is induced to the epithelial cells, and cytokines may disrupt cellular response to DNA damage and drives cell proliferation.