血液中甲基化的细胞周期蛋白 D2 基因作为肝细胞癌预后预测因子。

Methylated cyclin D2 gene circulating in the blood as a prognosis predictor of hepatocellular carcinoma.

机构信息

Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Ube, Japan.

出版信息

Clin Chim Acta. 2010 Apr 2;411(7-8):516-20. doi: 10.1016/j.cca.2010.01.004. Epub 2010 Jan 11.

DOI:10.1016/j.cca.2010.01.004

PMID:20064498

Abstract

BACKGROUND

Prognosis of hepatocellular carcinoma (HCC) remains poor because of high recurrence rate. We examined preoperatively the methylated CCND2 gene levels present in the serum following release from HCC cells as a prognosis predictor in patients undergoing curative hepatectomy.

METHODS

Quantitative real-time RT-PCR and quantitative methylation-specific PCR were used to measure methylated CCND2 gene and its mRNA levels.

RESULTS

The CCND2 mRNA levels were down-regulated in HCC with early intrahepatic recurrence (IHR) within 1year of curative hepatectomy. We also identified that this down-regulation was due to promoter hypermethylation. In 70 HCC patients who underwent curative hepatectomy, 39 patients sero-positive for the methylated CCND2 gene (>70pg/ml serum) exhibited a significantly shorter disease-free survival (DFS) period (P=0.02) than the 31 patients who were sero-negative for the methylated CCND2 gene. None of the sero-negative patients demonstrated early IHR, and this method of serum testing did not produce any false-negative predictions for early IHR. Multivariate analysis showed that the serum level of methylated CCND2 was an independent risk factor for DFS (hazard ratio of 1.866, 95% CI: 1.106-3.149).

CONCLUSION

Methylated CCND2 gene in the serum serves as a prognosis predictor of HCC after curative hepatectomy.

摘要

背景

由于肝癌（HCC）的高复发率，其预后仍然较差。我们在根治性肝切除术前检测 HCC 细胞释放到血清中的甲基化 CCND2 基因水平，作为预测患者预后的指标。

方法

采用实时定量 RT-PCR 和定量甲基化特异性 PCR 检测甲基化 CCND2 基因及其 mRNA 水平。

结果

在根治性肝切除术后 1 年内发生早期肝内复发（IHR）的 HCC 中，CCND2 mRNA 水平下调。我们还发现这种下调是由于启动子超甲基化所致。在 70 例接受根治性肝切除术的 HCC 患者中，39 例血清甲基化 CCND2 基因阳性（>70pg/ml 血清）的患者无病生存（DFS）期明显缩短（P=0.02），而 31 例血清甲基化 CCND2 基因阴性的患者则无此现象。所有血清甲基化 CCND2 基因阴性的患者均未发生早期 IHR，且该血清检测方法对早期 IHR 无假阴性预测。多变量分析显示，血清甲基化 CCND2 水平是 DFS 的独立危险因素（危险比为 1.866，95%CI：1.106-3.149）。