Gastroenterology

Gastroenterology

Volume 124, Issue 5, May 2003, Pages 1193-1201
Gastroenterology

Clinical-alimentary tract
Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms

https://doi.org/10.1016/S0016-5085(03)00157-4Get rights and content

Abstract

Background & Aims:

Genetic variations in proinflammatory and anti-inflammatory cytokine genes influence individual response to carcinogenic exposures. Polymorphisms in interleukin (IL)-1β 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 α and IL-10 were each associated with more than doubling of the risk of noncardia gastric cancer. Carriage of multiple proinflammatory polymorphisms of IL-1Bo 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.

Section snippets

Study population

The subjects in this study came from a multicenter, case-control study of esophageal and gastric cancer conducted in 3 geographic areas of the United States with population-based tumor registries.16 Population-based controls were frequency matched by 5-year age group and sex, and were selected by random-digit dialing and Health Care Financing Administration roster sampling as previously described.16 Genomic DNA was obtained from peripheral blood samples that had been collected at some of the

Results

Demographic and risk-factor characteristics of the subjects with cancer and the controls (Table 2) were similar to those reported in the previous study.16

Among controls, the alleles at all of the individual loci studied were in Hardy-Weinberg equilibrium, with nominally nonsignificant χ2 values (Table 3). Nevertheless, only 9 (4%) had the homozygous variant genotype of IL-1B-511, whereas 16 (7%) were expected based on allele frequencies (Hardy-Weinberg χ2 = 5.6; P = 0.07, 2 df). Based on

Discussion

We have identified a proinflammatory profile of genetic polymorphisms in IL-1B, IL-1RN, IL-10, and TNF-A associated with an increased risk of gastric cancer that was limited to noncardia tumors. No associations were seen with cancers of the gastric cardia or esophagus. The IL-1 gene cluster polymorphisms were associated with gastric cancer in 2 previous reports.11, 22 The ORs are similar in all 3 studies (all in predominantly white populations), underscoring the central role of IL-1β in the

References (43)

  • S.S. Devesa et al.

    Changing patterns in the incidence of esophageal and gastric carcinoma in the United States

    Cancer

    (1998)
  • R.M. Peek et al.

    Role of Helicobacter pylori cagA(+) strains and specific host immune responses on the development of premalignant and malignant lesions in the gastric cardia

    Int J Cancer

    (1999)
  • R.M. Peek et al.

    Helicobacter pylori and gastrointestinal tract adenocarcinomas

    Nat Rev Cancer

    (2002)
  • B.A. Ponder

    Cancer genetics

    Nature

    (2001)
  • J. Peto et al.

    Genetics and the common cancers

    Eur J Cancer

    (2001)
  • E.M. El-Omar et al.

    Interleukin-1 polymorphisms associated with increased risk of gastric cancer

    Nature

    (2000)
  • E.M. El-Omar

    The importance of interleukin 1beta in Helicobacter pylori associated disease

    Gut

    (2001)
  • J.L. Bidwell et al.

    Cytokine gene polymorphism in human disease: on-line databases

    (2002)
  • M.D. Gammon et al.

    Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia

    J Natl Cancer Inst

    (1997)
  • W.H. Chow et al.

    An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma

    Cancer Res

    (1998)
  • J.W. Holloway et al.

    Comparison of three methods for single nucleotide polymorphism typing for DNA bank studiessequence-specific oligonucleotide probe hybridisation, TaqMan liquid phase hybridisation, and microplate array diagonal gel electrophoresis (MADGE)

    Hum Mutat

    (1999)
  • Cited by (816)

    View all citing articles on Scopus

    Supported in part by the National Cancer Institute. E.M.E. received a European H. pylori Study Group Research Fellowship from the Digestive Disorders Foundation (United Kingdom).

    1

    The authors thank Drs. Heidi Rotterdam and Brian West for reviewing medical records and pathology slides for case eligibility, Dr. Denise Whitby for laboratory support, and Shelley Niwa for computing support.

    View full text