Aberrant Methylation Of Serum Cysteine Dioxygenase1(Cdo1) Gene Promoter In Primary Liver Cancer

Background and aimsPrimary liver cancer (PLC) is one of the most common cancers worldwide, both of the incidence and mortality rates are very high. Cysteine dioxygenase1(CDO1) is responsible for the conversion of cysteine to cysteine sulfinate and a key enzyme in the taurine biosynthetic pathway. The CDO1gene is a tumor suppressor and usually is silenced by the methylation of its promoter in carcinogenesis. In this study, we aimed to evaluate whether the methylation status of CDO1gene promoter is of diagnostic value for primary liver cancer.Patients and methodsA total of200subjects visiting the Qilu Hospital of Shandong University from July2011to December2012were consecutively enrolled, including123patients with primary liver cancer,28patients with liver cirrhosis (LC),29patients with chronic hepatitis B (CHB) and20healthy controls (HC). Patients with PLC were diagnosed based on the2010update of the American Association for the Study of Liver Disease (AASLD) practice guidelines for management of primary liver cancer. Patients with CHB and LC were diagnosed according to the2009update of AASLD practice guidelines for management of chronic hepatitis B. Serum CDO1promoter methylation status was determined using methylation specific polymerase chain reaction (MSP).Results1. The frequency of serum CDO1promoter methylation in PLC (42.3%) was significantly higher than that in LC (14.3%), CHB (6.9%) and HC (0%)(P=0.006; P <0.0001; P<0.0001; respectively). However, the frequencies of serum CDO1promoter methylation among LC patients, CHB patients and healthy controls showed no significant difference (LC vs. HC, P=0.130; CHB vs. HC, P=0.507; LC vs. CHB, P=0.363; respectively).2. In PLC patients, TNM Ⅲ-Ⅳ stages (53%) had higher frequency of CDO1promoter methylation than the TNM Ⅰ-Ⅱ stages (20%)(P=0.001). Furthermore, the serum CDO1promoter methylation was more frequent in PLC patients with tumors size>5cm (OR=3.834, P=0.001), multinodular tumors (OR=3.183, P=0.004) and portal or hepatic vein invasion (OR=4.04, P<0.0001).3. Evaluation of the CDO1promoter methylation status in serum, in combination with a-fetoprotein (AFP)(>20ng/ml), significantly improved the diagnostic value, with sensitivity and specificity of82.9%and75.4%, respectively in distinguishing PLC from LC and CHB.Conclusions Our study suggests that serum CDO1promoter methylation status could potentially serve as an additional biomarker for the diagnosis of PLC and assignment of the PLC stages.