Association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of esophageal squamous cell carcinoma

PLoS One. 2013 Dec 4;8(12):e81999. doi: 10.1371/journal.pone.0081999. eCollection 2013.

Abstract

Background: 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; 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.

Methods: We 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell / genetics*
  • Demography
  • Environment
  • Esophageal Neoplasms / genetics*
  • Esophageal Squamous Cell Carcinoma
  • Female
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Haplotypes / genetics
  • Humans
  • I-kappa B Proteins / genetics*
  • Linkage Disequilibrium / genetics
  • Lymph Nodes / pathology
  • Male
  • Middle Aged
  • Multivariate Analysis
  • NF-KappaB Inhibitor alpha
  • NF-kappa B p50 Subunit / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Prognosis
  • Risk Factors
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / genetics*

Substances

  • I-kappa B Proteins
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • NFKBIA protein, human
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha

Grants and funding

The authors acknowledge the fellowship grant from Indian Council of Medical Research, New Delhi. The funding agency had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.