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

Abstract

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.

Using circulating tumor DNA as a novel biomarker to screen and diagnose hepatocellular carcinoma: A systematic review and meta‐analysis

“…[60][61][62] Among these 33 publications, 11 articles described the diagnostic role of circulating Ras association domain family 1 isoform A (RASSF1A) methylation in HCC 37,39,40,[48][49][50]52,[60][61][62]65 and eight articles evaluated the diagnostic performance of ctDNA combined with AFP assay in HCC. 38,[40][41][42][43][44]54,56 Nine articles assessed the diagnostic accuracy of AFP assay for HCC 37,[40][41][42][43][44][62][63][64] Our study enrolled a total population of 2268 HCC patients and 1845 control individuals (1318 patients with benign liver disorders and 527 healthy volunteers). The primary characteristics of all participants are summarized in Table 1.…”

Prognostic significance of promoter DNA hypermethylation of the cysteine dioxygenase 1 (CDO1) gene in primary gallbladder cancer and gallbladder disease

“…We recently confirmed the CDO1 gene as being specifically methylated in various human cancers [ 8 ] following our development of an original algorithm designated as a pharmacological unmasking microarray (PUM), which suggested that CDO1 plays a tumor suppressive role in human carcinogenesis [ 5 ]. Promoter DNA of the CDO1 gene has been reported to be frequently methylated in various cancers, including breast [ 6 – 9 ], esophagus [ 11 ], lung [ 8 , 18 , 19 ], bladder [ 8 ], gastric [ 8 ], colorectal [ 8 , 20 ], biliary tract [ 13 ], hepatocyte [ 21 ], renal clear-cell cancer [ 10 ], and testicular germ cell cancers [ 22 ]. Furthermore, we previously described detection of CDO1 methylation in the plasma of colorectal cancer (CRC) using methylation specific PCR (Q-MSP) and extensive analysis of the PCR reaction [ 23 ].…”

Cysteine dioxygenase type 1 (CDO1) gene promoter methylation during the adenoma-carcinoma sequence in colorectal cancer

“…Methylation of the CDO1 promoter region has been found in esophageal cancer [ 8 , 10 ], gastric cancer [ 8 ], colorectal cancer [ 8 ], cholangiocarcinoma [ 11 ], lung cancer [ 8 , 12 ], breast cancer [ 8 ], bladder cancer [ 8 ], prostate cancer [ 13 ], endometrial cancer [ 14 ], and hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) [ 15 ]. The degree of malignancy or cancer progression with methylation has been reported for some cancers: gallbladder cancer [ 16 ], Barrett esophagus cancer [ 17 ], esophageal squamous cell carcinoma [ 10 ], and HBV-related HCC [ 15 ]. In breast cancer [ 18 ], gallbladder cancer [ 16 ], renal clear-cell cancer [ 19 ], esophageal squamous cell carcinoma [ 10 ], and lung cancer [ 20 ], methylation abnormalities in CDO1 have been reported as a prognostic factor.…”