Qian Yu, Wang He, Zhang Ying, Wang Jing-Wen, Fan Yu-Chen, Gao Shuai, Wang Kai
Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University.
Department of Hepatopathy, Qingdao Sixth People's Hospital.
Tohoku J Exp Med. 2021 Jul;254(3):233-243. doi: 10.1620/tjem.254.233.
Prognosis of patients with hepatocellular carcinoma remains poor because of progression of hepatocellular carcinoma and high recurrence rates. Cyclin D2 (CCND2) plays a vital role in regulating the cell cycle; indeed, aberrant methylation of CCND2 is involved in the development of hepatocellular carcinoma. Therefore, we aimed to investigate levels of CCND2 methylation in patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma and to evaluate its prognostic significance after hepatectomy. In total, 257 subjects were enrolled (166 hepatocellular carcinoma patients undergoing surgical resection, 61 chronic hepatitis B (CHB) patients, and 30 healthy controls). CCND2 methylation in peripheral blood mononuclear cells was measured quantitatively using MethyLight. We found that CCND2 methylation levels in patients with HBV-associated hepatocellular carcinoma were significantly higher than in CHB patients (P < 0.001) or healthy controls (P < 0.001). Within the hepatocellular carcinoma group, CCND2 methylation levels were higher in patients with portal vein invasion, early tumor recurrence, TNM III/IV stage, and tumor size ≥ 5 cm (P < 0.05). Furthermore, higher levels of CCND2 methylation were associated with worse overall survival and disease-free survival (P = 0.005 and P < 0.001, respectively). Multivariate analysis identified CCND2 methylation as an independent prognostic factor for early tumor recurrence (P = 0.021), overall survival (P = 0.022), and disease-free survival (P < 0.001) in hepatocellular carcinoma patients after resection. In conclusion, hypermethylation of CCND2 may have clinical utility for predicting a high risk of poor prognosis and early tumor recurrence in patients with HBV-associated hepatocellular carcinoma after hepatectomy.
由于肝细胞癌的进展和高复发率，肝细胞癌患者的预后仍然很差。细胞周期蛋白D2（CCND2）在调节细胞周期中起着至关重要的作用；事实上，CCND2的异常甲基化与肝细胞癌的发生发展有关。因此，我们旨在研究乙型肝炎病毒（HBV）相关肝细胞癌患者中CCND2的甲基化水平，并评估其肝切除术后的预后意义。总共纳入了257名受试者（166名接受手术切除的肝细胞癌患者、61名慢性乙型肝炎（CHB）患者和30名健康对照）。使用甲基化特异性荧光定量PCR法定量检测外周血单个核细胞中的CCND2甲基化。我们发现，HBV相关肝细胞癌患者的CCND2甲基化水平显著高于CHB患者（P < 0.001）或健康对照（P < 0.001）。在肝细胞癌组中，门静脉侵犯、早期肿瘤复发、TNM III/IV期和肿瘤大小≥5 cm的患者CCND2甲基化水平较高（P < 0.05）。此外，较高水平的CCND2甲基化与较差的总生存期和无病生存期相关（分别为P = 0.005和P < 0.001）。多因素分析确定CCND2甲基化为肝切除术后肝细胞癌患者早期肿瘤复发（P = 0.021）、总生存期（P = 0.022）和无病生存期（P < 0.001）的独立预后因素。总之，CCND2的高甲基化可能对预测HBV相关肝细胞癌患者肝切除术后预后不良和早期肿瘤复发的高风险具有临床应用价值。
