Tohoku J. Exp. Med., 2021 July, 254(3)

Hypermethylation of Cyclin D2 Predicts Poor Prognosis of Hepatitis B Virus-Associated Hepatocellular Carcinoma after Hepatectomy

Yu Qian,1 He Wang,2 Ying Zhang,1 Jing-Wen Wang,1 Yu-Chen Fan,1,3 Shuai Gao1,3 and Kai Wang1,3

1Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
2Department of Hepatopathy, Qingdao Sixth People's Hospital, Qingdao, Shandong, China
3Institute of Hepatology, Shandong University, Jinan, Shandong, China

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.

Key words —— cyclin D2; early tumor recurrence; hepatocellular carcinoma; methylation; prognosis


Tohoku J. Exp. Med 2021, 254, 233-243.

Correspondence: Kai Wang, M.D., Ph.D., Department of Hepatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University; Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan Shandong 250012, China.