Epigenetic priming in chronic liver disease impacts the transcriptional and genetic landscapes of hepatocellular carcinoma. Issue 3 (29th December 2021)

• Record Type: Journal Article
• Authors: Gallon, John; Coto‐Llerena, Mairene; Ercan, Caner; Bianco, Gaia; Paradiso, Viola; Nuciforo, Sandro; Taha‐Melitz, Stephanie; Meier, Marie‐Anne; Boldanova, Tujana; Pérez‐del‐Pulgar, Sofía; Rodríguez‐Tajes, Sergio; von Flüe, Markus; Soysal, Savas D.; Kollmar, Otto; Llovet, Josep M.; Villanueva, Augusto; Terracciano, Luigi M.; Heim, Markus H.; Ng, Charlotte K. Y.; Piscuoglio, Salvatore
• Is Part Of: Molecular oncology. Volume 16:Issue 3(2022)
• Page Start: 665
• Page End: 682
• Publication Date: 2021-12-29
• Subjects: chronic liver disease -- epigenetic priming -- hepatocellular carcinoma -- methylation; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.13154
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : 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. Abstract : Precancerous cells in chronically diseased livers (CLD) may be 'epigenetically primed', sensitising them to oncogenic transformation. We investigated whether epigenetic priming in CLD also affects hepatocellular carcinoma (HCC) outcome. We found this sculpts the HCC transcriptome, creating an environment favouring the acquisition of genetic alterations. Our DNA methylation‐based score shows the extent to which epigenetic priming occurs in CLD and influences HCC outcome.