Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Gastric Cancer. 2012 Oct;15(4):382-8. doi: 10.1007/s10120-011-0126-1. Epub 2012 Jan 12.
Epigenomic damage induced by Helicobacter pylori infection is accumulated in gastric mucosae before the development of malignancy. In individuals without current H. pylori infection, DNA methylation levels of specific CpG islands (CGIs) are associated with gastric cancer risk. Because risk estimation in individuals with past infection is clinically important, we here aimed to identify the risk markers that reflect epigenomic damage induced by H. pylori infection, and that are informative in these individuals.
Gastric mucosae were obtained from 55 gastric cancer patients (GC-Pt) (21 with current infection and 34 with past infection) and 55 healthy volunteers (HV) (7 never-infected, 21 with current infection, and 27 with past infection). Hypermethylated CGIs were searched for by methylated DNA immunoprecipitation-CGI microarray, and methylation levels were analyzed by quantitative methylation-specific polymerase chain reaction (PCR).
By microarray analysis of a pool of three samples from GC-Pt with past infection and another pool of samples from HV with past infection, 15 hypermethylated CGIs in the former pool were isolated. Seven of them had significantly higher methylation levels in GC-Pt with past infection (n = 10) than in HV with past infection (n = 10) (P < 0.001). In a validation cohort (21 GC-Pt with past infection and 14 HV with past infection), the seven new markers had large areas under the receiver-operating characteristic curves (0.78-0.84) and high odds ratios (12.7-36.0) compared with two currently available markers (0.60-0.65, 5.0-5.7).
We identified seven novel gastric cancer risk markers that are highly informative in individuals with past infection.
幽门螺杆菌感染引起的表观基因组损伤在恶性肿瘤发生前就已在胃黏膜中积累。在没有当前幽门螺杆菌感染的个体中，特定 CpG 岛（CGI）的 DNA 甲基化水平与胃癌风险相关。由于对既往感染者的风险评估在临床上很重要，因此，我们旨在确定反映幽门螺杆菌感染引起的表观基因组损伤的风险标志物，并在这些个体中提供信息。
从 55 名胃癌患者（GC-Pt）（21 名现症感染者和 34 名既往感染者）和 55 名健康志愿者（HV）（7 名从未感染者、21 名现症感染者和 27 名既往感染者）中获得胃黏膜。通过甲基化 DNA 免疫沉淀-CGI 微阵列搜索超甲基化 CGI，并通过定量甲基化特异性聚合酶链反应（PCR）分析甲基化水平。
通过对来自既往感染 GC-Pt 的三个样本池和来自既往感染 HV 的另一个样本池的微阵列分析，从前者池中共分离出 15 个超甲基化 CGI。其中 7 个在既往感染 GC-Pt（n=10）中的甲基化水平明显高于既往感染 HV（n=10）（P<0.001）。在验证队列（21 名既往感染 GC-Pt 和 14 名既往感染 HV）中，与两个现有的标志物（0.60-0.65，5.0-5.7）相比，这七个新标志物的受试者工作特征曲线下面积（0.78-0.84）较大，优势比（12.7-36.0）较高。
我们鉴定了 7 个新型胃癌风险标志物，在既往感染者中具有高度信息性。
