Abstract PURPOSE: Genetic alterations in inflammatory genes are associated with chronic inflammatory bowel disease, a well-known risk factor for colorectal cancer (CRC). The purpose of this study was to investigate the association between alterations in inflammatory NFκB signaling pathway genes and CRC susceptibility and survival. EXPERIMENTAL DESIGN: Using 344 CRC cases and 793 randomly selected healthy individuals from southeastern Sweden, we examined seven polymorphisms in NFκB, TNFAIP3, NLRP3, CARD8 and TLR4 genes. Chi-square tests and multiple logistic regression analysis were used to test for associations between the SNPs and CRC susceptibility, while log-rank tests and Cox proportional hazard regression were used to examine the association between the SNPs and CRC-specific survival. Loss of heterozygosity and mutational analyses of TNFAIP3 were carried out in 137 and 79 tumors, respectively. RESULTS: Adjusted for age, gender and polypoid/ulcerative CRC phenotype, a panel of heterozygous and mutant TNFAIP3 (rs6920220), mutant NF B −94 ATTG ins/del and heterozygous NLRP3 (Q705K) was associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2 95% CI 2.5-10.9, P < 0.001). Continuous or partial LOH of 6q23.3, the location of the TNFAIP3 gene was detected in 17% of the colorectal tumors while mutations in TNFAIP3 were detected in two out of 79 colorectal tumors (2.5%). CONCLUSIONS: We propose TNFAIP3 as a novel tumor suppressor in CRC and also present evidence that a panel of the TNFAIP3 (rs6920220), NF B −94 ATTG ins/del and NLRP3 (Q705K) polymorphisms could be used as a prognostic marker to identify patients at high risk for rapid CRC progression and poor survival. 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 1154. doi:1538-7445.AM2012-1154