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

Research output: Contribution to journalArticle

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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

Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. / Argent, Richard H.; Thomas, Rachael J.; Aviles-Jimenez, Francisco; Letley, Darren P.; Limb, Marie C.; El-Omar, Emad M.; Atherton, John C.

In: Clinical Cancer Research, Vol. 14, No. 7, 01.04.2008, p. 2227-2235.

Research output: Contribution to journalArticle

Argent, Richard H. ; Thomas, Rachael J. ; Aviles-Jimenez, Francisco ; Letley, Darren P. ; Limb, Marie C. ; El-Omar, Emad M. ; Atherton, John C. / Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 7. pp. 2227-2235.
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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.",
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T1 - Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families

AU - Argent, Richard H.

AU - Thomas, Rachael J.

AU - Aviles-Jimenez, Francisco

AU - Letley, Darren P.

AU - Limb, Marie C.

AU - El-Omar, Emad M.

AU - Atherton, John C.

PY - 2008/4/1

Y1 - 2008/4/1

N2 - 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.

AB - 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.

KW - achlorhydria

KW - adult

KW - aged

KW - antigens, bacterial

KW - bacterial proteins

KW - DNA fingerprinting

KW - family

KW - female

KW - Helicobacter infections

KW - Helicobacter pylori

KW - humans

KW - male

KW - middle aged

KW - pedigree

KW - precancerous conditions

KW - reverse transcriptase polymerase chain reaction

KW - Stomach neoplasms

KW - virulence

KW - vacuolating cytotoxin

KW - epithelial-cells

KW - tyrosine phosphorylation

KW - caga genotypes

KW - duodenal-ulcer

KW - increased risk

KW - 3' region

KW - vaca

KW - strains

KW - disease

U2 - 10.1158/1078-0432.CCR-07-2022

DO - 10.1158/1078-0432.CCR-07-2022

M3 - Article

VL - 14

SP - 2227

EP - 2235

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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ER -