CpG island hypermethylation of tumor-suppressor genes in H. pylori-infected non-neoplastic gastric mucosa is linked with gastric cancer risk.
OBJECTIVE
Gastric carcinogenesis involves CpG island hypermethylation (CIHM) of tumor-suppressor genes. Although the CIHM of these genes occurs in non-neoplastic gastric cells, it is unclear whether this epigenetic alteration is linked with aging and/or gastric cancer risk. We investigated this linkage in noncancerous gastric mucosa infected with H. pylori.


METHODS
Noncancerous corpus mucosa was endoscopically obtained from H. pylori-positive gastric cancer patients (n = 34), and age-matched H. pylori-positive noncancerous controls (n = 68). Genomic DNA retrieved from the mucosa was subjected to methylation-specific polymerase chain reaction for p16, Ecad, and DAPK genes. Linkage between CIHM and clinicopathologic factors was evaluated.


RESULTS
CIHM rates of DAPK, Ecad, and p16 promoters were significantly higher in noncancerous gastric mucosa of gastric cancer patients (91, 88, and 68%, respectively) than in noncancerous controls (71, 53, and 25%, respectively). Multivariate regression analysis showed a significant linkage between CIHM in noncancerous mucosa and coexistence of gastric cancer. Significant linkage between polymorphoneutrophil infiltration and CIHM was observed except for CIHM of p16. No linkage was observed between CIHM and other parameters, including age. High CIHM status (all three tested genes methylated) was associated with an increased risk of gastric cancer, with an odds ratio of 9.8 (95% confidence interval, 3.8-25.3).


CONCLUSIONS
In a subset of the H. pylori-infected population, CIHM of tumor-suppressor genes in noncancerous gastric mucosa is linked with the risk of gastric cancer and polymorphoneutrophil infiltration, but not aging. CIHM is a potential marker of gastric cancer risk.
Kaise
Mitsuru
M
Department of Endoscopy, The Jikei University School of Medicine, Tokyo, Japan. kaise@jikei.ac.jp
Yamasaki
Takuji
T
Yonezawa
Jin
J
Miwa
Jun
J
Ohta
Yasuhiko
Y
Tajiri
Hisao
H
D000328:Adult; D000367:Age Factors; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001706:Biopsy; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases; D005260:Female; D005753:Gastric Mucosa / Q000737:chemistry* / Q000473:pathology; D005773:Gastroscopy; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D025521:Tumor Suppressor Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases