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 language | English |
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Pages (from-to) | 2227-2235 |
Number of pages | 9 |
Journal | Clinical Cancer Research |
Volume | 14 |
Issue number | 7 |
DOIs | |
Publication status | Published - 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