Epigenetic priming in chronic liver disease impacts the transcriptional and genetic landscapes of hepatocellular carcinoma

John Gallon, Mairene Coto-Llerena, Caner Ercan, Gaia Bianco, Viola Paradiso, Sandro Nuciforo, Stephanie Taha-Melitz, Marie Anne Meier, Tujana Boldanova, Sofía Pérez-del-Pulgar, Sergio Rodríguez-Tajes, Markus von Flüe, Savas D. Soysal, Otto Kollmar, Josep M. Llovet, Augusto Villanueva, Luigi M. Terracciano, Markus H. Heim, Charlotte K.Y. Ng, Salvatore Piscuoglio

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Hepatocellular carcinomas (HCCs) usually arise from chronic liver disease (CLD). Precancerous cells in chronically inflamed environments may be ‘epigenetically primed’, sensitising them to oncogenic transformation. We investigated whether epigenetic priming in CLD may affect HCC outcomes by influencing the genomic and transcriptomic landscapes of HCC. Analysis of DNA methylation arrays from 10 paired CLD-HCC identified 339 shared dysregulated CpG sites and 18 shared differentially methylated regions compared with healthy livers. These regions were associated with dysregulated expression of genes with relevance in HCC, including ubiquitin D (UBD), cytochrome P450 family 2 subfamily C member 19 (CYP2C19) and O-6-methylguanine-DNA methyltransferase (MGMT). Methylation changes were recapitulated in an independent cohort of nine paired CLD-HCC. High CLD methylation score, defined using the 124 dysregulated CpGs in CLD and HCC in both cohorts, was associated with poor survival, increased somatic genetic alterations and TP53 mutations in two independent HCC cohorts. Oncogenic transcriptional and methylation dysregulation is evident in CLD and compounded in HCC. Epigenetic priming in CLD sculpts the transcriptional landscape of HCC and creates an environment favouring the acquisition of genetic alterations, suggesting that the extent of epigenetic priming in CLD could influence disease outcome.

Original languageEnglish
Pages (from-to)665-682
Number of pages18
JournalMolecular Oncology
Issue number3
StatePublished - Feb 2022


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