Liver Cancer Research Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Hepatology. 2015 Jun;61(6):1945-56. doi: 10.1002/hep.27732. Epub 2015 Mar 18.
Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma (HCC) and of the potential role of DNA methylation markers as prognostic biomarkers. Analysis of tumor tissue from 304 patients with HCC treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array (Illumina, Inc., San Diego, CA), which covers 96% of known cytosine-phosphate-guanine (CpG) islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate (Affymetrix, Inc., Santa Clara, CA) and miRNA Chip 2.0. Random survival forests enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient survival both in the training (221 patients; 47% hepatitis C-related HCC) and validation sets (n = 83; 47% alcohol-related HCC). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known to be deregulated by aberrant methylation in HCC (e.g., Ras association [RalGDS/AF-6] domain family member 1, insulin-like growth factor 2, and adenomatous polyposis coli) and other solid tumors (e.g., NOTCH3) and describes potential candidate epidrivers (e.g., septin 9 and ephrin B2).
A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with HCC. Patients with this methylation profile harbor messenger RNA-based signatures indicating tumors with progenitor cell features.
表观遗传失调已成为人类恶性肿瘤的驱动因素。目前尚不清楚肝细胞癌 (HCC) 中的表观遗传改变，以及 DNA 甲基化标记作为预后生物标志物的潜在作用。对 304 例接受手术切除治疗的 HCC 患者的肿瘤组织进行分析，我们使用训练-验证方案生成了基于甲基化的预后特征。采用 Illumina HumanMethylation450 阵列 (Illumina，Inc.，圣地亚哥，CA) 进行甲基组谱分析，该阵列覆盖 96%已知的胞嘧啶-磷酸-鸟嘌呤 (CpG) 岛和 485,000 个 CpG；采用 Affymetrix Human Genome U219 板 (Affymetrix，Inc.，圣克拉拉，CA) 和 miRNA Chip 2.0 进行转录组谱分析。随机生存森林使我们能够基于 36 个甲基化探针生成甲基化特征。我们为每个个体计算了一个死亡率风险评分，该评分能够准确区分训练集 (221 例患者；47%为丙型肝炎相关 HCC) 和验证集 (n=83；47%为酒精相关 HCC) 中患者的生存情况。该特征与已知的不良预后预测因子相关，保留了与多结节性和血小板计数相关的独立预后能力。该特征识别的患者子集富含具有祖细胞特征的增殖分子亚型。该研究证实了 HCC (如 Ras 相关 [RalGDS/AF-6] 结构域家族成员 1、胰岛素样生长因子 2 和腺瘤性结肠息肉病) 和其他实体瘤 (如 NOTCH3) 中已知因异常甲基化而失调的基因的高患病率，并描述了潜在的候选表观遗传驱动基因 (如 septin 9 和 ephrin B2)。
经过验证的 36 个 DNA 甲基化标记的特征准确预测了 HCC 患者的不良生存。具有这种甲基化特征的患者具有基于信使 RNA 的特征，表明肿瘤具有祖细胞特征。
