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

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 Gao^1,3 and Kai Wang^1,3

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.

Keywords —— cyclin D2; early tumor recurrence; hepatocellular carcinoma; methylation; prognosis

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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.

e-mail: wangdoc876@126.com