Quantitative Analysis of Circulating Methylated DNA as a Biomarker for Hepatocellular Carcinoma

Hypermethylation of the RASSF1A [Ras association (RalGDS/AF-6) domain family member 1A] gene is frequently observed in hepatocellular carcinoma (HCC). We evaluated the analysis of circulating hypermethylated RASSF1A for detecting HCC and assessing its prognosis. In module 1, we studied 63 pairs of H...

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Bibliographic Details
Published in:Clinical chemistry (Baltimore, Md.) Md.), 2008-09, Vol.54 (9), p.1528-1536
Main Authors: Chan, K. C. Allen, Lai, Paul B. S, Mok, Tony S. K, Chan, Henry L. Y, Ding, Chunming, Yeung, S. W, Lo, Y. M. Dennis
Format: Article
Language:English
Subjects:
alpha-Fetoproteins - metabolism
Analytical, structural and metabolic biochemistry
Base Sequence
Biological and medical sciences
Biomarkers, Tumor - blood
Biomarkers, Tumor - genetics
Blood
Cancer
Carcinoma, Hepatocellular - blood
Carcinoma, Hepatocellular - etiology
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - surgery
Disease-Free Survival
DNA Methylation
DNA, Circular - analysis
DNA, Circular - genetics
Female
Fundamental and applied biological sciences. Psychology
Hepatitis B - blood
Hepatitis B - complications
Hepatitis B - genetics
Hepatitis B virus - physiology
Hepatology
Hospitals
Humans
Investigative techniques, diagnostic techniques (general aspects)
Liver Cirrhosis - blood
Liver Cirrhosis - genetics
Male
Medical sciences
Middle Aged
Patients
Surveillance
Time Factors
Tropical diseases
Tumor Suppressor Proteins - blood
Tumors
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Summary:Hypermethylation of the RASSF1A [Ras association (RalGDS/AF-6) domain family member 1A] gene is frequently observed in hepatocellular carcinoma (HCC). We evaluated the analysis of circulating hypermethylated RASSF1A for detecting HCC and assessing its prognosis. In module 1, we studied 63 pairs of HCC patients and age- and sex-matched chronic hepatitis B virus (HBV) carriers, as well as 50 healthy volunteers. In module 2, we studied 22 HCC patients with cancer detected through a surveillance program. The concentrations of circulating hypermethylated RASSF1A sequences were measured by real-time PCR after digestion with a methylation-sensitive restriction enzyme. We detected hypermethylated RASSF1A sequences in the sera of 93% of HCC patients, 58% of HBV carriers, and 8% of the healthy volunteers. The median RASSF1A concentrations for the HCC patients and HBV carriers were 7.70 x 10(5) copies/L and 1.18 x 10(5) copies/L, respectively (P < 0.01). The detection of low concentrations in HBV carriers is consistent with previous findings that RASSF1A hypermethylation is an early event in HCC pathogenesis and can be found in premalignant liver tissues. Use of a marker cutoff value of 1 x 10(6) copies/L also identifies 50% of alpha-fetoprotein-negative HCC cases. Patients with higher RASSF1A concentrations at diagnosis or 1 year after tumor resection showed poorer disease-free survival (P < 0.01). For the HBV carriers who underwent HCC surveillance and subsequently developed HCC, the circulating concentration of RASSF1A increased significantly from the time of enrollment to cancer diagnosis (P = 0.014). Detection and quantification of circulating methylated RASSF1A sequences are useful for HCC screening, detection, and prognostication.
ISSN:0009-9147
1530-8561
DOI:10.1373/clinchem.2008.104653