TY - JOUR
T1 - Epigenetic priming in chronic liver disease impacts the transcriptional and genetic landscapes of hepatocellular carcinoma
AU - Gallon, John
AU - Coto-Llerena, Mairene
AU - Ercan, Caner
AU - Bianco, Gaia
AU - Paradiso, Viola
AU - Nuciforo, Sandro
AU - Taha-Melitz, Stephanie
AU - Meier, Marie Anne
AU - Boldanova, Tujana
AU - Pérez-del-Pulgar, Sofía
AU - Rodríguez-Tajes, Sergio
AU - von Flüe, Markus
AU - Soysal, Savas D.
AU - Kollmar, Otto
AU - Llovet, Josep M.
AU - Villanueva, Augusto
AU - Terracciano, Luigi M.
AU - Heim, Markus H.
AU - Ng, Charlotte K.Y.
AU - Piscuoglio, Salvatore
N1 - Funding Information:
LMT, CKYN and SP were supported by the Swiss Cancer League (KLS‐3639‐02‐2015, KFS‐4543‐08‐2018 and KFS‐4988‐02‐2020‐R, respectively); LMT was supported by AIRC grant number IG 2019 Id.23615. SP was supported by the Professor Dr Max Cloëtta Foundation, from the University of Basel (Research Fund Junior Researchers), from the Krebsliga Beider Basel (KLbB‐4473‐03‐2018), from the Theron Foundation, Vaduz (LI) and from the Surgery Department of the University Hospital Basel. MHH was supported by ERC Synergy Grant 609883. JML was supported by grants from the European Commission (EC) Horizon 2020 Program (HEPCAR, proposal number 667273‐2), the US Department of Defense (CA150272P3), the National Cancer Institute (P30 CA196521), the Samuel Waxman Cancer Research Foundation and the Spanish National Health Institute (MICINN, SAF‐2016‐76390 and PID2019‐105378RB‐I00), and through a partnership between Cancer Research UK, Fondazione AIRC and Fundación Científica de la Asociacion Española Contra el Cáncer (HUNTER, Ref. C9380/A26813), and by the Generalitat de Catalunya (AGAUR, SGR‐1358). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Funding Information:
LMT, CKYN and SP were supported by the Swiss Cancer League (KLS-3639-02-2015, KFS-4543-08-2018 and KFS-4988-02-2020-R, respectively); LMT was supported by AIRC grant number IG 2019 Id.23615. SP was supported by the Professor Dr Max Clo?tta Foundation, from the University of Basel (Research Fund Junior Researchers), from the Krebsliga Beider Basel (KLbB-4473-03-2018), from the Theron Foundation, Vaduz (LI) and from the Surgery Department of the University Hospital Basel. MHH was supported by ERC Synergy Grant 609883. JML was supported by grants from the European Commission (EC) Horizon 2020 Program (HEPCAR, proposal number 667273-2), the US Department of Defense (CA150272P3), the National Cancer Institute (P30 CA196521), the Samuel Waxman Cancer Research Foundation and the Spanish National Health Institute (MICINN, SAF-2016-76390 and PID2019-105378RB-I00), and through a partnership between Cancer Research UK, Fondazione AIRC and Fundaci?n Cient?fica de la Asociacion Espa?ola Contra el C?ncer (HUNTER, Ref. C9380/A26813), and by the Generalitat de Catalunya (AGAUR, SGR-1358). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Funding Information:
AV has received consulting fees from Guidepoint, Fujifilm, Boehringer Ingelheim, FirstWord and MHLife Sciences; advisory board fees from Exact Sciences, Nucleix, Gilead and NGM Pharmaceuticals; and research support from Eisai. JML has received consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol‐Myers Squibb, Eisai Inc., Celsion Corporation, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha Ltd and AstraZeneca; and research support from Bayer HealthCare Pharmaceuticals, Eisai Inc., Bristol‐Myers Squibb, Boehringer Ingelheim and Ipsen.
Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122107612&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.13154
DO - 10.1002/1878-0261.13154
M3 - Article
C2 - 34863035
AN - SCOPUS:85122107612
SN - 1574-7891
VL - 16
SP - 665
EP - 682
JO - Molecular Oncology
JF - Molecular Oncology
IS - 3
ER -