Abstract
BackgroundTumour necrosis factor-alpha (TNF-α) and nuclear factor of kappa light chain gene enhancer in activated B cells (NF-κB) play critical role in carcinogenesis processes like tumour initiation, proliferation, migration and invasion. Single nucleotide polymorphisms in TNF-α, NF-κB and its inhibitor IκB genes were shown to be associated with susceptibility and prognosis of several cancers; however, their role in esophageal squamous cell carcinoma (ESCC) is not well recognised. Therefore, in present study, we aimed to investigate association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of ESCC in northern Indian population. MethodsWe genotyped 290 ESCC patients (including 162 followed up cases) and 311 mean age, gender and ethnicity matched controls for TNFA -308G>A, NFkB1 -94ATTG ins/del and NFKBIA (-826C>T and 3’UTRA>G) polymorphisms using PCR alone or followed by RFLP and TaqMan assay.Results TNFA -308GA genotype was associated with increased risk of ESCC specifically in females and in patients with regional lymph node involvement, while, NFKBIA -826CT+TT genotype conferred decreased risk of ESCC in females. Haplotypes of NFKBIA -826C>T and 3’UTRA>G polymorphisms, C-826G3’UTR and T-826A3’UTR, were associated with reduced risk of ESCC. No independent role of NFkB1 -94ATTG ins/del polymorphism in susceptibility of ESCC was found. Multi-dimensionality reduction analysis showed three factor model TNFA-308, NFKBIA-826, NFKBIA 3’UTR as better predictor for risk of ESCC. Furthermore, combined risk genotype analysis of all studied polymorphisms showed increased risk of ESCC in patients with 1-3 risk genotype compared to ‘0’ risk genotype. Survival analysis did not show any significant prognostic effect of studied polymorphisms. However, in stepwise multivariate analysis, metastasis was found to be independent prognostic predictor of ESCC patients.Conclusion TNFA-308 and NFKBIA (-826C>T and 3’UTRA>G) polymorphisms may play role in susceptibility but not in prognosis of ESCC patients in northern Indian population.
Highlights
Chronic inflammation, a critical component of tumour microenvironment, is involved in pathogenesis of approximately 25% of all human cancers including esophageal cancer (EC) [1,2]
Several functional polymorphisms are present in the promoter region of TNFA; the most documented single nucleotide polymorphism (SNP) is located at 308 nucleotide position resulting in substitution of G to A
In the present study, we investigated the association of TNFA-308 G>A, NFKB1 -94ATTG ins/del and NFKBIA (-826 C>T and 3’UTR A>G) polymorphisms with susceptibility to esophageal squamous cell carcinoma (ESCC) or its clinical phenotypes, their interaction with environmental risk factors and their role in survival outcome of ESCC patients
Summary
A critical component of tumour microenvironment, is involved in pathogenesis of approximately 25% of all human cancers including esophageal cancer (EC) [1,2]. Tumour necrosis factor-alpha (TNF-α) and nuclear factor of kappa light chain gene enhancer in activated B cells (NF-κB) play critical role in carcinogenesis processes like tumour initiation, proliferation, migration and invasion. Single nucleotide polymorphisms in TNF-α, NF-κB and its inhibitor IκB genes were shown to be associated with susceptibility and prognosis of several cancers; their role in esophageal squamous cell carcinoma (ESCC) is not well recognised. In present study, we aimed to investigate association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of ESCC in northern Indian population. Conclusion: TNFA-308 and NFKBIA (-826C>T and 3’UTRA>G) polymorphisms may play role in susceptibility but not in prognosis of ESCC patients in northern Indian population
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