基于全基因组高分辨率芯片的胃癌 DNA 甲基化的临床意义分析。
Analysis of the clinical significance of DNA methylation in gastric cancer based on a genome-wide high-resolution array.
机构信息
Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd, Beitou District, Taipei City, Taiwan, 11217.
School of Medicine, National Yang-Ming University, Taipei City, Taiwan, 11217.
出版信息
Clin Epigenetics. 2019 Nov 1;11(1):154. doi: 10.1186/s13148-019-0747-5.
BACKGROUND
Aberrant DNA methylation is involved in gastric carcinogenesis and may serve as a useful biomarker in the diagnosis and detection of gastric cancer (GC) recurrence.
RESULTS
A total of 157 patients who received surgery for GC were enrolled in the present study. A genome-wide methylation analysis was performed in tumor and adjacent normal tissues for the discovery set of 16 GC patients; the top three hypermethylated CpG sites of DNA promoters were selected for validation in tissue and plasma samples for the validation set of 141 GC patients. The frequencies of the top three hypermethylated genes in available patient tissues (n = 141) and plasma samples (n = 106) were 41.8% and 38.7%, respectively, for ADAM19; 40.4% and 42.5%, respectively, for FLI1; and 56.7% and 50.9%, respectively, for MSC. In both tissue and plasma samples, FLI1 hypermethylation was associated with more advanced GC and liver and distant lymphatic metastasis, and ADAM19 hypermethylation was associated with more stage IV GC. In plasma samples, MSC hypermethylation was more common in non-superficial type GC than samples without MSC hypermethylation. In both tissue and plasma samples, patients with methylation of all the three genes had significantly more liver metastases, distant lymphatic metastases, and paraaortic lymph node metastases than patients with two or fewer hypermethylated genes. The survival analysis showed that only for stage III GC, patients with hypermethylation of two or three genes had a worse 5-year disease-free survival rate than those with hypermethylation of one or none of the three genes. Subgroup analysis showed that FLI1 hypermethylation in both tissue and plasma samples was associated with liver metastasis in MSI-/EBV- GC, and MSC hypermethylation in tissue samples was correlated with liver metastasis in MSI+ or EBV+ GC. Patients with FLI1 hypermethylation in plasma samples had a significantly worse 5-year disease-free survival rate than those without FLI1 hypermethylation in MSI-/EBV- GC. FLI1 hypermethylation was an independent prognostic factor affecting the overall survival and disease-free survival in both tissue and plasma samples.
CONCLUSIONS
DNA methylation is a useful biomarker for predicting tumor recurrence patterns and GC patient survival.
背景
异常的 DNA 甲基化参与胃癌的发生，并且可能作为诊断和检测胃癌（GC）复发的有用生物标志物。
结果
本研究共纳入 157 例接受 GC 手术的患者。对 16 例 GC 患者的发现集进行肿瘤和相邻正常组织的全基因组甲基化分析；选择前三个 DNA 启动子高甲基化的 CpG 位点在 141 例 GC 患者的组织和血浆样本中进行验证。在可获得的患者组织（n=141）和血浆样本（n=106）中，前三个高甲基化基因的频率分别为 ADAM19 的 41.8%和 38.7%、FLI1 的 40.4%和 42.5%以及 MSC 的 56.7%和 50.9%。在组织和血浆样本中，FLI1 甲基化与 GC 更晚期、肝转移和远处淋巴结转移相关，ADAM19 甲基化与更晚期的 IV 期 GC 相关。在血浆样本中，非浅表型 GC 中 MSC 甲基化比无 MSC 甲基化的 GC 更常见。在组织和血浆样本中，所有三个基因甲基化的患者肝转移、远处淋巴结转移和腹主动脉旁淋巴结转移的发生率明显高于两个或两个以下基因甲基化的患者。生存分析表明，仅在 III 期 GC 中，两个或三个基因甲基化的患者 5 年无病生存率低于一个或三个基因均未甲基化的患者。亚组分析表明，组织和血浆样本中 FLI1 甲基化与 MSI-/EBV-GC 的肝转移相关，组织样本中 MSC 甲基化与 MSI+或 EBV+ GC 的肝转移相关。血浆样本中 FLI1 甲基化的患者 5 年无病生存率明显低于 MSI-/EBV-GC 中无 FLI1 甲基化的患者。FLI1 甲基化是影响组织和血浆样本中总生存和无病生存的独立预后因素。
结论
DNA 甲基化是预测肿瘤复发模式和 GC 患者生存的有用生物标志物。
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