title: Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer.
abstract: Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor-kappa B (NFκB) is a major regulator of inflammation and variation in NFκB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFκB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.
authors: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, SE-581 85, Linkoping, Sweden. jonas.ungerback@liu.se
authors: Jonas
authors: J
authors: Ungerbäck
authors: Dimitri
authors: D
authors: Belenki
authors: Aksa
authors: A
authors: Jawad ul-Hassan
authors: Mats
authors: M
authors: Fredrikson
authors: Karin
authors: K
authors: Fransén
authors: Nils
authors: N
authors: Elander
authors: Deepti
authors: D
authors: Verma
authors: Peter
authors: P
authors: Söderkvist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013548:Sweden; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3