title: Accumulation of aberrant CpG hypermethylation by Helicobacter pylori infection promotes development and progression of gastric MALT lymphoma.
abstract: Aberrant DNA hypermethylation is an important mechanism for the inactivation of tumor-related genes in human tumors. Gastric mucosa-associated lymphoid tissue (MALT) lymphomas arise from Helicobacter pylori-associated chronic gastritis; most patients are H. pylori-positive and eradication therapy is highly effective. In the present study, we used methylation-specific PCR to analyze the DNA methylation status of 11 tumor-related genes (Kip2, p16, hMLH-1, p15, p73, MGMT, DAPK, MINT1, MINT2, MINT31 and HCAD) in 21 specimens of MALT lymphoma, 5 specimens of MALT lymphoma with large cell component (high-grade MALT lymphoma), 15 specimens of diffuse large B-cell lymphoma (DLBCL), 8 specimens of complete remission of MALT lymphoma after eradication therapy, 5 specimens with no evidence of malignancy and PBMCs from 10 healthy donors. The average number of methylated genes was significantly greater in gastric lymphomas as compared to normal controls (P<0.001). The CpG island methylator phenotype (CIMP) was observed in 93.3% (14/15) of DLBCLs, 100% (5/5) of high-grade MALT lymphomas and 61.9% (13/21) of MALT lymphomas; in contrast, CIMP was not found in the control group (0%). The average number of methylated genes and the CIMP incidence significantly increased with H. pylori infection. Furthermore, aberrant CpG methylation of specific genes, such as p16, MGMT and MINT31, was consistently associated with H. pylori infection. These findings strongly suggest that H. pylori infection causes the aberrant DNA hypermethylation of specific genes and induces CIMP, which is an important epigenetic mechanism for the development and progression of gastric MALT lymphoma; additionally, our findings provide new epigenetic markers.
authors.affiliation: Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Takami
authors.initials: T
authors.lastname: Kondo
authors.forename: Takashi
authors.initials: T
authors.lastname: Oka
authors.forename: Hiaki
authors.initials: H
authors.lastname: Sato
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shinnou
authors.forename: Kana
authors.initials: K
authors.lastname: Washio
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takano
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Morito
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Takata
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ohara
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ouchida
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
mesh_terms: D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D018450:Disease Progression; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics; D016480:Helicobacter pylori; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000821:virology*; D016133:Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000821:virology*