CDKN2A 启动子甲基化与肿瘤位置和组织学亚型有关，并与胃腺癌中的幽门螺杆菌 flaA(+)菌株相关。

CDKN2A promoter methylation is related to the tumor location and histological subtype and associated with Helicobacter pylori flaA(+) strains in gastric adenocarcinomas.

机构信息

Microbiology Section, Department of Pathology and Forensic Medicine, Federal University of Ceará, Porangabussu Campus, Ceará, Brazil.

出版信息

APMIS. 2010 Apr;118(4):297-307. doi: 10.1111/j.1600-0463.2010.02591.x.

DOI:10.1111/j.1600-0463.2010.02591.x

PMID:20402675

Abstract

Promoter hypermethylation of CDKN2A (p16INK4A protein) is the main mechanism of gene inactivation. However, its association with Helicobacter pylori infection is a controversial issue. Therefore, we examined a series of gastric adenocarcinomas to assess the association between p16INK4A inactivation and H. pylori genotype (vacA, cagA, cagE, virB11 and flaA) according to the location and histological subtype of the tumors. p16INK4A expression and CDKN2A promoter methylation were found in 77 gastric adenocarcinoma samples by immunohistochemistry and methylation-specific PCR, respectively. Helicobacter pylori infection and genotype were determined by PCR. A strong negative correlation between immunostaining and CDKN2A promoter region methylation was found. In diffuse subtype tumors, the inactivation of p16INK4A by promoter methylation was unique in noncardia tumors (p=0.022). In addition, H. pylori-bearing flaA was associated with non-methylation tumors (p=0.008) and H. pylori strain bearing cagA or vacAs1m1 genes but without flaA was associated with methylated tumors (p=0.022 and 0.003, respectively). Inactivation of p16INK4A in intestinal and diffuse subtypes showed distinct carcinogenic pathways, depending on the tumor location. Moreover, the process of methylation of the CDKN2A promoter seems to depend on the H. pylori genotype. The present data suggest that there is a differential influence and relevance of H. pylori genotype in gastric cancer development.

摘要

CDKN2A（p16INK4A 蛋白）启动子的高甲基化是基因失活的主要机制。然而，其与幽门螺杆菌感染的关系是一个有争议的问题。因此，我们检查了一系列胃腺癌，根据肿瘤的位置和组织学亚型，评估 p16INK4A 失活与幽门螺杆菌基因型（vacA、cagA、cagE、virB11 和 flaA）之间的关联。通过免疫组织化学和甲基化特异性 PCR 分别在 77 个胃腺癌样本中发现 p16INK4A 表达和 CDKN2A 启动子甲基化。通过 PCR 确定幽门螺杆菌感染和基因型。免疫染色与 CDKN2A 启动子区域甲基化之间存在强烈的负相关。在弥漫型肿瘤中，非贲门肿瘤中 p16INK4A 的启动子甲基化失活是独特的（p=0.022）。此外，携带 flaA 的幽门螺杆菌与非甲基化肿瘤相关（p=0.008），而携带 cagA 或 vacAs1m1 基因但不携带 flaA 的幽门螺杆菌菌株与甲基化肿瘤相关（p=0.022 和 0.003）。肠型和弥漫型肿瘤中 p16INK4A 的失活表现出不同的致癌途径，这取决于肿瘤的位置。此外，CDKN2A 启动子的甲基化过程似乎取决于幽门螺杆菌的基因型。本研究数据表明，幽门螺杆菌基因型在胃癌发展中存在不同的影响和相关性。