Kondo Takami, Oka Takashi, Sato Hiaki, Shinnou Yoko, Washio Kana, Takano Masayuki, Morito Toshiaki, Takata Katsuyoshi, Ohara Nobuya, Ouchida Mamoru, Shimizu Kenji, Yoshino Tadashi
Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Int J Oncol. 2009 Sep;35(3):547-57. doi: 10.3892/ijo_00000366.
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.
异常的DNA高甲基化是人类肿瘤中肿瘤相关基因失活的重要机制。胃黏膜相关淋巴组织（MALT）淋巴瘤起源于幽门螺杆菌相关的慢性胃炎；大多数患者幽门螺杆菌呈阳性，根除治疗非常有效。在本研究中，我们使用甲基化特异性PCR分析了21例MALT淋巴瘤标本、5例伴有大细胞成分的MALT淋巴瘤标本（高级别MALT淋巴瘤）、15例弥漫性大B细胞淋巴瘤（DLBCL）标本、8例根除治疗后MALT淋巴瘤完全缓解的标本、5例无恶性证据的标本以及10名健康供者的外周血单核细胞（PBMC）中11个肿瘤相关基因（Kip2、p16、hMLH-1、p15、p73、MGMT、DAPK、MINT1、MINT2、MINT31和HCAD）的DNA甲基化状态。与正常对照相比，胃淋巴瘤中甲基化基因的平均数量显著增加（P<0.001）。在93.3%（14/15）的DLBCL、100%（5/5）的高级别MALT淋巴瘤和61.9%（13/21）的MALT淋巴瘤中观察到CpG岛甲基化表型（CIMP）；相比之下，对照组未发现CIMP（0%）。甲基化基因的平均数量和CIMP发生率随幽门螺杆菌感染显著增加。此外，特定基因如p16、MGMT和MINT31的异常CpG甲基化与幽门螺杆菌感染始终相关。这些发现强烈表明，幽门螺杆菌感染导致特定基因的异常DNA高甲基化并诱导CIMP，这是胃MALT淋巴瘤发生和发展的重要表观遗传机制；此外，我们的发现提供了新的表观遗传标志物。
