Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families

Richard H. Argent, Rachael J. Thomas, Francisco Aviles-Jimenez, Darren P. Letley, Marie C. Limb, Emad M. El-Omar, John C. Atherton

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34 Citations (Scopus)

Abstract

Purpose: Helicobacter pylori infection by virulent strains is associated with gastric adenocarcinoma. We aimed to determine whether infection with virulent H pylori preceeded precancerous gastric hypochlorhydria and atrophy in gastric cancer relatives and quantify the extent of virulence factor evolution.

Experimental Design: H pylori strains from 51 Scottish gastric cancer relatives were characterized by genetic fingerprinting and typing the vacuolating cytotoxin gene (vacA), the cytotoxin-associated gene (cagA), and housekeeping genes. We phenotyped strains by coculture with gastric epithelial cells and assessing vacuolation (microscopy), CagA tyrosine phosphorylation (immunoblot), and interleukin-8 secretion (ELISA).

Results: Toxigenic (vacA type s1/m1) H pylori was associated with precancerous gastric hypochlorhydria (P < 0.01). Adult family members with this type of H pylori had the same strain as currently noncohabiting adult family members in 68% cases, implying acquisition during childhood from each other or a common source. We analyzed different isolates of the same strain within families and showed that H pylori commonly microevolved to change virulence: this occurred in 22% individuals and a striking 44% cases where the strain was shared within families. Microevolution in vacA occurred by extragenomic recombination and in cagA by this or duplication/deletion. Microevolution led to phenotypic changes in virulence. Passage of microevolved strains could be tracked within families.

Conclusions: Toxigenic H. pylori infection precedes and so likely causes gastric hypochlorhydria, suggesting that virulent H pylori increases cancer risk by causing this condition. Microevolution of virulence genes is common within families of gastric cancer patients and changes H pylori virulence.

Original languageEnglish
Pages (from-to)2227-2235
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number7
DOIs
Publication statusPublished - 1 Apr 2008

Keywords

  • achlorhydria
  • adult
  • aged
  • antigens, bacterial
  • bacterial proteins
  • DNA fingerprinting
  • family
  • female
  • Helicobacter infections
  • Helicobacter pylori
  • humans
  • male
  • middle aged
  • pedigree
  • precancerous conditions
  • reverse transcriptase polymerase chain reaction
  • Stomach neoplasms
  • virulence
  • vacuolating cytotoxin
  • epithelial-cells
  • tyrosine phosphorylation
  • caga genotypes
  • duodenal-ulcer
  • increased risk
  • 3' region
  • vaca
  • strains
  • disease

Cite this

Argent, R. H., Thomas, R. J., Aviles-Jimenez, F., Letley, D. P., Limb, M. C., El-Omar, E. M., & Atherton, J. C. (2008). Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. Clinical Cancer Research, 14(7), 2227-2235. https://doi.org/10.1158/1078-0432.CCR-07-2022