Circulating cell-free DNA species affect the risk of hepatocellular carcinoma in treated chronic hepatitis B patients

Alkistis Papatheodoridi, Antonios Chatzigeorgiou, Lampros Chrysavgis, Panagiotis Lembessis, Alessandro Loglio, Floriana Facchetti, Evangelos Cholongitas, Michael Koutsilieris, Pietro Lampertico, George Papatheodoridis

Research output: Contribution to journalArticlepeer-review


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 an indicator of DNA methylation was performed. HCC cases compared with controls had higher median levels of Alu247 (123 vs 69 genomic equivalent, p =.042) and RNase P coding DNA (68 vs 15 genomic equivalent, p <.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 <.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.

Original languageEnglish
Pages (from-to)464-474
Number of pages11
JournalJournal of Viral Hepatitis
Issue number3
Publication statusPublished - Mar 2021


  • cirrhosis
  • hepatitis B
  • liver cancer
  • senescence
  • therapy

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases
  • Virology


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