Methylated Cysteine Dioxygenase-1 Gene Promoter in the Serum Is a Potential Biomarker for Hepatitis B Virus-Related Hepatocellular Carcinoma

Methylated Cysteine Dioxygenase-1 Gene Promoter in the Serum Is a Potential Biomarker for Hepatitis B Virus-Related Hepatocellular Carcinoma

YANG YANG,^1,2 YU-CHEN FAN,^1,2 SHUAI GAO,¹ CHENG-YUN DOU,¹ JIAN-JUN ZHANG,¹ FENG-KAI SUN¹ and KAI WANG^1,2

¹Department of Hepatology, Qilu Hospital of Shandong University, Jinan, P.R. China
²Institute of Hepatology, Shandong University, Jinan, P.R. China

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Epigenetic analysis has attracted increasing attention in the molecular diagnosis of HCC. Cysteine dioxygenase 1 (CDO1) is a key enzyme in the taurine biosynthetic pathway and converts cysteine to cysteine sulfinate. The CDO1 gene is a tumor suppressor gene and is usually silenced by the methylation of its promoter in carcinogenesis. In this study, we evaluated whether the methylation status of CDO1 gene promoter is of diagnostic value for hepatitis B virus (HBV)-related HCC. The CDO1 promoter methylation status was determined in serum samples using methylation-specific polymerase chain reaction (MSP) in a cohort of 123 patients with HBV-related HCC, 28 with liver cirrhosis (LC), 29 with chronic hepatitis B (CHB) and 20 healthy controls. The frequency of the CDO1 promoter methylation in HBV-related HCC (42.3%) was significantly higher than that in LC (14.3%), CHB (6.9%) and healthy controls (0%) (P = 0.006; P < 0.0001; P < 0.0001; respectively). Furthermore, in HCC patients, the frequency of CDO1 promoter methylation was higher in advanced stages (III-IV) (53%) than the early stages (I-II) (20%) (P = 0.001). Evaluation of the CDO1 promoter methylation status in serum, in combination with AFP (> 20 ng/ml), significantly improved the diagnostic value, with sensitivity and specificity of 82.9% and 75.4%, respectively in distinguishing HCC from LC and CHB. In conclusion, methylation status of serum CDO1 gene promoter may be helpful in the diagnosis of HCC and the estimation of the HCC stages.

keywords —— α-fetoprotein; cysteine dioxygenase 1; hepatitis B virus; hepatocellular carcinoma; methylation

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Tohoku J. Exp. Med., 2014, 232, 187-194

Correspondence: Kai Wang, M.D., Ph.D., Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Wenhuaxi Road 107 #, Jinan 250012, P.R. China.

e-mail: wangdoc876@126.com; wangdoc2010@163.com