血浆中 CpG 岛甲基化表型与肝细胞癌预后相关。
CpG island methylator phenotype in plasma is associated with hepatocellular carcinoma prognosis.
机构信息
Institute of Life Sciences, Jiangsu University, Zhenjiang 212013, Jiangsu Province, China.
出版信息
World J Gastroenterol. 2011 Nov 14;17(42):4718-24. doi: 10.3748/wjg.v17.i42.4718.
AIM
To evaluate the clinical significance of CpG island methylator phenotype (CIMP) in plasma and its association with hepatocellular carcinoma (HCC) progress.
METHODS
CIMP status of 108 HCC patients was analyzed using a methylation marker panel in tumor tissues and plasma with methylation-specific polymerase chain reaction. Fifteen samples of non-neoplastic liver tissues and 60 of plasma from healthy persons were examined simultaneously. Examined genes included APC, WIF-1, RUNX-3, DLC-1, SFRP-1, DKK and E-cad.
RESULTS
The frequencies of high-level methylation in HCC tissue and plasma were at least 15% for the seven genes: APC, 48/108, 44.44% in tissue and 26/108, 24.07% in plasma; WIF-1, 53/108, 49.07% in tissue and 35/108, 32.41% in plasma; RUNX-3, 52/108, 48.14% in tissue and 42/108, 38.89% in plasma; DLC-1, 38/108, 35.18% in tissue and 23/108, 21.30% in plasma; SFRP-1, 40/108, 37.04% in tissue and 31/108, 28.7% in plasma; DKK, 39/108, 36.1% in tissue and 25/108, 23.14% in plasma; and E-cad, 37/108, 34.3% in tissue and 18/108, 16.67% in plasma. CIMP+ (≥ 3 methylated genes) was detected in 68 (60.2%) tumor tissue samples and 62 (57.4%) plasma samples. CIMP was not detected in non-neoplastic liver tissues or plasma of healthy persons. CIMP status in tumor tissues differed significantly in gender, hepatitis B surface antigen, alpha-fetoprotein, and tumor-node-metastasis stage (P < 0.05). Similar results were obtained with plasma samples (P < 0.05). There was no difference in CIMP status in age, presence of hepatitis C virus antibody, cirrhosis, number of nodes, number of tumors, tumor size, or Edmondson-Steiner stage. A one-year follow-up found that the metastatic rate and recurrence rate in the CIMP+ group were significantly higher than in the CIMP- group as assessed with plasma samples (P < 0.05).
CONCLUSION
Plasma DNA can be a reliable sample source for CIMP analysis. CIMP in plasma may serve as a molecular marker of late-stage and poor-prognosis HCC.
目的
评估血浆中 CpG 岛甲基化表型（CIMP）的临床意义及其与肝细胞癌（HCC）进展的关系。
方法
采用甲基化特异性聚合酶链反应，对 108 例 HCC 患者肿瘤组织和血浆中的 CIMP 状态进行分析。同时检测了 15 例非肿瘤性肝组织和 60 例健康人血浆样本。检测的基因包括 APC、WIF-1、RUNX-3、DLC-1、SFRP-1、DKK 和 E-cad。
结果
在 HCC 组织和血浆中，7 个基因的高甲基化频率至少为 15%：APC，48/108，44.44%在组织中，26/108，24.07%在血浆中；WIF-1，53/108，49.07%在组织中，35/108，32.41%在血浆中；RUNX-3，52/108，48.14%在组织中，42/108，38.89%在血浆中；DLC-1，38/108，35.18%在组织中，23/108，21.30%在血浆中；SFRP-1，40/108，37.04%在组织中，31/108，28.70%在血浆中；DKK，39/108，36.1%在组织中，25/108，23.14%在血浆中；E-cad，37/108，34.3%在组织中，18/108，16.67%在血浆中。在 68 例（60.2%）肿瘤组织样本和 62 例（57.4%）血浆样本中检测到 CIMP+（≥3 个甲基化基因）。在非肿瘤性肝组织或健康人血浆中未检测到 CIMP。肿瘤组织中的 CIMP 状态在性别、乙型肝炎表面抗原、甲胎蛋白和肿瘤-淋巴结-转移分期方面存在显著差异（P<0.05）。血浆样本也得到了类似的结果（P<0.05）。CIMP 状态与年龄、丙型肝炎病毒抗体、肝硬化、节点数、肿瘤数、肿瘤大小或 Edmondson-Steiner 分期无关。对患者进行了一年的随访，结果发现 CIMP+组的转移率和复发率明显高于 CIMP-组（P<0.05）。
结论
血浆 DNA 可以作为 CIMP 分析的可靠样本来源。血浆中的 CIMP 可能是 HCC 晚期和预后不良的分子标志物。
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