Simple SummaryColon cancer is one of the common cancers affecting a large number of patients globally. In sporadic CRC, several genetic factors may play important roles such as genetic mutations, genetic instability, and DNA promoter methylation. However, the role of inflammatory pathogenesis of sporadic CRC is less widely appreciated. Ulcerative colitis (UC) provides a unique opportunity to identify genes dysregulated in colon inflammation in human subjects and to exploit those pathways as a proxy of inflammation. In this study, we identified a number of such dysregulated metabolic and other pathways in UC and demonstrated that many of those inflammation-related gene pathways were also associated with sporadic CRC. The findings from US patients were also replicated in Bangladeshi patients with CRC. We demonstrate that this “inflammation—cancer” association was independent of sex and conventional genetic factors. The study widens our understanding of CRC pathogenesis and some of these dysregulated pathways may provide useful therapeutic options in the future.AbstractThe association of chronic inflammation with colorectal carcinoma (CRC) development is well known in ulcerative colitis (UC). However, the role of inflammatory changes in sporadic CRC pathogenesis is less widely appreciated. In this study, in the first step using RNA-seq, we identified gene-pathway-level changes in UC-associated CRC (UC CRC,n= 10) and used the changes as a proxy for inflammation in human colon to ask if there were associations of inflammatory pathway dysregulations in sporadic CRC pathogenesis (n= 8). We found down-regulations of several inflammation-related metabolic pathways (nitrogen metabolism, sulfur metabolism) and other pathways (bile secretion, fatty acid degradation) in sporadic CRC. Non-inflammation-related changes included up-regulation of the proteasome pathway. In the next step, from a larger number of paired samples from sporadic CRC patients (n= 71) from a geographically and ethnically different population and using a different platform (microarray), we asked if the inflammation-CRC association could be replicated. The associations were significant even after stratification by sex, tumor stage, grade, MSI status, andKRASmutation status. Our findings have important implications to widen our understanding of inflammatory pathogenesis of sporadic CRC. Furthermore, targeting of several of these dysregulated pathways could provide the basis for improved therapies for CRC.