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- Ungerbäck, Jonas, et al.
(författare)
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Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer
- 2012
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Ingår i: Carcinogenesis. - Oxford, United kingdom : Oxford University Press. - 0143-3334 .- 1460-2180. ; 33:11, s. 2126-2134
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Ungerbäck, Jonas, et al.
(författare)
-
Genetic variation in NFκB signaling pathway genes in colorectal cancer susceptibility and survival
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- PURPOSE: Variations in genes orchestrating inflammatory responses, such as those being connected with NFκB and NLRP3 inflammasome signaling, are associated with chronic inflammatory bowel diseases, which are well-known risk factors for colorectal cancer (CRC). The purpose of this study was to investigate the association between genetic variation and alterations in genes involved in NFκB and NLRP3 inflammasome signaling and their possible influence on susceptibility and clinical outcome of colorectal cancer. EXPERIMENTAL DESIGN: 344 CRC cases and 793 randomly selected healthy individuals from southeastern Sweden were examined with regard to 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 analysis were used to examine the association between the SNPs and CRC-specific survival. Gene expression assay and loss of heterozygosity analyzes of TNFAIP3 were carried out in a subset of tumors to assess its role as a potential tumor suppressor in CRC. RESULTS: Adjusted for age, gender and polypoid/ulcerative CRC phenotype, a panel of heterozygous and mutant TNFAIP3 (rs6920220), mutant NFκB -94 ATTG ins/del and heterozygous NLRP3 (Q705K) 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 to adjacent non-neoplastic mucosa (P < 0.0001) and LOH of 6q23.3, (TNFAIP3), was detected in 17% of cases, while only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. CONCLUSIONS: A panel of the TNFAIP3 (rs6920220), NFκB -94 ATTG ins/del and NLRP3 (Q705K) polymorphisms are associated with poor survival in patients with advanced CRC and may be used as a prognostic marker. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.
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