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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
Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
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2012 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 33, no 11, p. 2126-2134Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford, United kingdom: Oxford University Press, 2012. Vol. 33, no 11, p. 2126-2134
National Category
Cancer and Oncology
Research subject
Biomedicine; Oncology
Identifiers
URN: urn:nbn:se:oru:diva-27489DOI: 10.1093/carcin/bgs256ISI: 000310624400014PubMedID: 22843550Scopus ID: 2-s2.0-84868626486OAI: oai:DiVA.org:oru-27489DiVA, id: diva2:604134
Funder
Swedish Research Council, 2010-55X-20451-04-3Available from: 2013-02-07 Created: 2013-02-07 Last updated: 2018-08-28Bibliographically approved

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Fransén, Karin

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