TNF-α gene promoter polymorphisms and risk of venous thromboembolism in gastrointestinal cancer patients undergoing chemotherapy

Ann Oncol. 2013 Oct;24(10):2571-2575. doi: 10.1093/annonc/mdt251. Epub 2013 Jul 12.

Abstract

Background: TNF-α has been proposed as a predictive factor for venous thromboembolism (VTE). Genetic polymorphisms could regulate TNF-α production. However, the relationship between TNFA gene variants and VTE is not clarified. This study aims to investigate the predictive role of five different TNFA gene promoter SNPs, or their haplotype combination(s), for a first VTE episode in gastrointestinal cancer out-patients treated with chemotherapy.

Patients and methods: Serum TNF-α levels and TNFA -863C/A, -857C/T, -376G/A, -308G/A and -238G/A gene promoter polymorphisms were retrospectively evaluated in 314 subjects, including 157 controls and 157 Caucasian patients with histologically diagnosed GI cancers beginning chemotherapy delivery (5-fluorouracil either as monotherapy or in combination with platinum compounds or irinotecan).

Results: Haplotype analysis showed that a five-loci haplotype (CTGGG haplotype) has higher frequency in GI cancer patients who developed VTE (n = 15) during chemotherapy [odds ratio = 2.7, 95% confidence interval (CI) 1.04-7.11, P = 0.04]. GI patients who remained VTE-free did not differ in CTGGG haplotype frequency from controls. No association was observed between serum TNF-α levels and TNFA haplotype, but both were independent predictors of VTE. Approximately 20% of GI cancer patients carrying the CTGGG haplotype developed VTE compared with 4% of the remaining 101 patients (hazard ratio = 5.6, 95% CI 1.8-17.6, P = 0.003).

Conclusion: These results suggest that TNFA might represent a candidate gene contributing to VTE pathogenesis in GI cancer patients and suggest that VTE risk during chemotherapy might be genetically identified. Validation studies are needed for translation into clinical practice.

Keywords: chemotherapy; gastrointestinal cancer; single nucleotide polymorphisms; tumour necrosis factor-α; venous thromboembolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antineoplastic Agents, Phytogenic / adverse effects
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Camptothecin / adverse effects
  • Camptothecin / analogs & derivatives
  • Camptothecin / therapeutic use
  • Case-Control Studies
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / therapeutic use
  • Gastrointestinal Neoplasms / drug therapy*
  • Genetic Predisposition to Disease
  • Haplotypes / genetics
  • Humans
  • Irinotecan
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics
  • Retrospective Studies
  • Risk
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics*
  • Venous Thromboembolism / chemically induced*
  • Venous Thromboembolism / genetics*

Substances

  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • Tumor Necrosis Factor-alpha
  • Irinotecan
  • Fluorouracil
  • Camptothecin