CpG Island Methylator Phenotype Associated with Tumor Recurrence in Tumor-Node-Metastasis Stage I Hepatocellular Carcinoma
CpG Island Methylator Phenotype Associated with Tumor Recurrence in Tumor-Node-Metastasis Stage I Hepatocellular Carcinoma
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CpG 岛甲基化表型与 I 期肝细胞癌肿瘤淋巴结转移相关
DOI：
10.1245/s10434-010-0921-7
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发表时间：
2010-07-01
影响因子：
3.7
通讯作者：
Yuan, Yunfei
中科院分区：
文献类型：
--
作者：
Li, Binkui;Liu, Wenji;Yuan, Yunfei
CpG岛甲基化表型(CIMP)以多个肿瘤抑制基因(TSG)同时甲基化为特征，已被报道与多种肿瘤的生物学恶性有关。利用甲基化特异性聚合酶链式反应检测115例肝细胞癌和48例非肿瘤性肝组织中10个TSGs和CIMP的甲基化状态。在肝细胞癌中，10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%，RARβ59.1%，SOCS-1和OPCML分别为82.6%和80.9%。115例肝细胞癌组织中有68例(59.1%)表达CIMP+(含6个或6个以上甲基化基因)，48例非肿瘤性肝组织中未检测到CIMP+。在分层单因素分析中，I期肝癌患者的总生存期(OS)(P=0.002)和无复发生存期(RF)(P=0.042)均明显短于CIMP+组。此外，多因素分析显示，CIMP+是TNMI期患者OS[风险比(HR)，12.266；P=0.015]和RFS(HR，2.275；P=0.032)的独立预后因素，CIMP+可特异性地定义一组预后不良的患者。CIMP状态的检测可能有助于对早期肝细胞癌患者的预后进行分层，并确定哪些患者具有较高的复发风险。
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.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.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 RAR beta, 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.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.