Genetic variation and alterations of genes involved in NFκ/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer
Menée dans le sud-est de la Suède sur 338 patients atteints d'un cancer colorectal et sur 806 témoins en bonne santé, cette étude montre une association entre des variants ou des altérations de gènes impliqués dans la voie de signalisation NFκ/TNFAIP3 ou de l'inflammasome NLRP3 et la survie des patients
Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustains several cancer hallmarks. NFκ is a major regulator of inflammation and variation in NFκ-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 NFκ pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival while 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 NFκ -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 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. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκ -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.
Carcinogenesis , résumé, 2012