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

¹ State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, Departments of ² Chemical Pathology, ³ Surgery, ⁴ Clinical Oncology, and ⁵ Medicine and Therapeutics, ⁶ Stanley Ho Centre for the Emerging Infectious Diseases, and ⁷ Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region, China.

^aAddress correspondence to this author at: Department of Chemical Pathology, Rm. 38023, 1/F, Clinical Science Building, Prince of Wales Hospital, 30-32 Ngan Shing St., Shatin, New Territories, Hong Kong SAR. Fax +852 2636 5090; e-mail loym{at}cuhk.edu.hk.

Background: 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.

Methods: 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.

Results: 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 10⁵ copies/L and 1.18 x 10⁵ 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 10⁶ copies/L also identifies 50% of -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).

Conclusions: Detection and quantification of circulating methylated RASSF1A sequences are useful for HCC screening, detection, and prognostication.

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