Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients even under effective long-term oral antiviral therapy, but its pathogenesis in the setting of long-standing inhibition of viral replication has not been completely elucidated. We investigated whether species of circulating cell-free DNA (cfDNA) may be involved in the process of hepatocarcinogenesis in treated CHB patients. Serum samples were obtained from HBeAg-negative CHB patients with (HCC cases, n=37) or without HCC development during the first 5 years of oral antiviral therapy (controls, n=74). HCC cases and controls were matched 1:2 for age, sex and platelets. Determination of different circulating cfDNA species (before HCC diagnosis in HCC cases) including total cfDNA quantity, levels of Alu repeat DNA and RNAse P coding DNA, copies of mitochondrial DNA and levels of 5-methyl-2′-deoxycytidine as indicator of DNA methylation was performed. HCC cases compared to controls had higher median levels of Alu247 (123 vs 69 genomic equivalent, P=0.042) and RNAse P coding DNA (68 vs 15 genomic equivalent, P<0.001). In contrast, median cfDNA concentration, Alu115 levels, Alu247/Alu115 ratio as an index of DNA integrity and mitochondrial DNA copies did not differ significantly between HCC cases and controls. Receiver operating characteristic curve analysis showed that levels RNAse P coding DNA offered good prediction of subsequent HCC development (c-statistic: 0.80, P<0.001). In conclusion, serum levels of RNAse P coding DNA are increased years before HCC diagnosis and could be potentially helpful in the prediction of the HCC risk in treated HBeAg-negative CHB patients.
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