Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms

Gastroenterology. 2003 May;124(5):1193-201. doi: 10.1016/s0016-5085(03)00157-4.


Background & aims: Genetic variations in proinflammatory and anti-inflammatory cytokine genes influence individual response to carcinogenic exposures. Polymorphisms in interleukin (IL)-1 beta and its endogenous receptor antagonist are associated with risk of Helicobacter pylori-related gastric cancer. The aim of this study was to evaluate the role of proinflammatory cytokine gene polymorphisms in gastric and esophageal cancers defined by anatomic subsite.

Methods: We assessed polymorphisms of the IL-1 gene cluster and 4 other cytokine genes in a population-based case-control study of upper gastrointestinal cancers, including gastric cardia (n = 126) and noncardia adenocarcinoma (n = 188), esophageal squamous cell carcinoma (n = 53), and adenocarcinoma (n = 108), and frequency-matched controls (n = 212). ORs for the different cancers were computed from logistic regression models adjusted for potential confounding factors.

Results: Proinflammatory genotypes of tumor necrosis factor alpha and IL-10 were each associated with more than doubling of the risk of noncardia gastric cancer. Carriage of multiple proinflammatory polymorphisms of IL-1B(o) IL-1 receptor antagonist, tumor necrosis factor A, and IL-10 conferred greater risk, with ORs (and 95% confidence intervals) of 2.8 (1.6-5.1) for one, 5.4 (2.7-10.6) for 2, and 27.3 (7.4-99.8) for 3 or 4 high-risk genotypes. In contrast, these polymorphisms were not consistently related to the risks of esophageal or gastric cardia cancers. Polymorphisms in IL-4 and IL-6 were not associated with any of the cancers studied.

Conclusions: A proinflammatory cytokine genetic profile increases the risk of noncardia gastric adenocarcinoma but not other upper gastrointestinal cancers, possibly by inducing a hypochlorhydric and atrophic response to gastric H. pylori infection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genotype
  • Helicobacter Infections / epidemiology
  • Helicobacter Infections / genetics
  • Helicobacter Infections / immunology
  • Helicobacter pylori
  • Humans
  • Interleukin-1 / genetics*
  • Interleukin-10 / genetics
  • Interleukin-4 / genetics
  • Interleukin-6 / genetics
  • Male
  • Middle Aged
  • Multigene Family
  • Polymorphism, Genetic*
  • Risk Factors
  • Stomach Neoplasms / epidemiology*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / immunology
  • Tumor Necrosis Factor-alpha / genetics


  • Interleukin-1
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4