CpG 岛甲基化表型与肿瘤复发相关，与肿瘤-淋巴结-转移分期 I 期肝细胞癌相关。

CpG island methylator phenotype associated with tumor recurrence in tumor-node-metastasis stage I hepatocellular carcinoma.

机构信息

Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.

出版信息

Ann Surg Oncol. 2010 Jul;17(7):1917-26. doi: 10.1245/s10434-010-0921-7. Epub 2010 Jan 29.

DOI:10.1245/s10434-010-0921-7

PMID:20112070

Abstract

BACKGROUND

CpG island methylator phenotype (CIMP), characterized by simultaneous methylation of multiple tumor suppressor genes (TSGs), has been reported to be associated with biological malignancy in many cancers. Whether CIMP is potentially predictive of clinical outcome in hepatocellular carcinoma (HCC) remains unknown.

METHODS

We investigated the methylation status of ten TSGs and CIMP in 115 samples of HCC and 48 samples of corresponding nonneoplastic liver tissues using a methylation-specific polymerase chain reaction.

RESULTS

The methylation frequencies of the ten genes examined in HCC were 40.0% for p14 ( ARF ), 60.9% for p15 ( INK4b ), 70.4% for p16 ( INK4a ), 34.8% for p73, 70.4% for GSTP1, 64.3% for MGMT, 13.0% for hMLH1, 59.1% for RARbeta, 82.6% for SOCS-1, and 80.9% for OPCML. CIMP+ (with six or more methylated genes) was detected in 68 (59.1%) of 115 HCCs and none of 48 nonneoplastic liver tissues. On stratified univariate analysis, patients with tumor-node-metastasis (TNM) stage I HCC with CIMP+ had significantly shorter overall survival (OS) (P = 0.002) and recurrence-free survival (RFS) (P = 0.042) than those with CIMP-. Furthermore, multivariate analysis revealed CIMP+ as an independent prognostic factor for both OS [hazard ratio (HR), 12.266; P = 0.015] and RFS (HR, 2.275; P = 0.032) in TNM stage I patients.

CONCLUSIONS

CIMP+ may specifically define a subgroup of patients with unfavorable outcome in TNM stage I HCC. Examination of CIMP status may be useful for stratifying prognosis of patients with early-stage HCC and identifying patients who are at higher risk for recurrence.

摘要

背景

CpG 岛甲基化表型（CIMP）的特征是多个肿瘤抑制基因（TSGs）的同时甲基化，已被报道与许多癌症的生物学恶性有关。CIMP 是否可能预测肝细胞癌（HCC）的临床结局尚不清楚。

方法

我们使用甲基化特异性聚合酶链反应（MSP）研究了 115 例 HCC 样本和 48 例相应非肿瘤性肝组织中 10 个 TSG 的甲基化状态和 CIMP。

结果

在 HCC 中，十个基因的甲基化频率分别为 p14（ARF）40.0%，p15（INK4b）60.9%，p16（INK4a）70.4%，p73 34.8%，GSTP1 70.4%，MGMT 64.3%，hMLH1 13.0%，RARbeta 59.1%，SOCS-1 82.6%和 OPCML 80.9%。在 115 例 HCC 中有 68 例（59.1%）检测到 CIMP+（有六个或更多甲基化基因），而在 48 例非肿瘤性肝组织中均未检测到。在分层单因素分析中，具有 CIMP+的肿瘤-淋巴结-转移（TNM）I 期 HCC 患者的总生存期（OS）（P = 0.002）和无复发生存期（RFS）（P = 0.042）显著短于 CIMP-患者。此外，多因素分析显示 CIMP+是 TNM I 期患者 OS（危险比（HR），12.266；P = 0.015）和 RFS（HR，2.275；P = 0.032）的独立预后因素。