Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach

Davide Gentilini, Stefania Scala, Germano Gaudenzi, Paolo Garagnani, Miriam Capri, Matteo Cescon, Gian Luca Grazi, Maria Giulia Bacalini, Serena Pisoni, Alessandra Dicitore, Luisa Circelli, Sara Santagata, Francesco Izzo, Anna Maria Di Blasio, Luca Persani, Claudio Franceschi, Giovanni Vitale

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) results from accumulation of both genetic and epigenetic alterations. We investigated the genome-wide DNA methylation profile in 69 pairs of HCC and adjacent non-cancerous liver tissues using the Infinium HumanMethylation 450K BeadChip array. An innovative analytical approach has been adopted to identify Stochastic Epigenetic Mutations (SEMs) in HCC. HCC and peritumoral tissues showed a different epigenetic profile, mainly characterized by loss of DNA methylation in HCC. Total number of SEMs was significantly higher in HCC tumor (median: 77,370) than in peritumoral (median: 5,656) tissues and correlated with tumor grade. A significant positive association emerged between SEMs measured in peritumoral tissue and hepatitis B and/or C virus infection status. A restricted number of SEMs resulted to be shared by more than 90% of HCC tumor samples and never present in peritumoral tissue. This analysis allowed the identification of four epigenetically regulated candidate genes (AJAP1, ADARB2, PTPRN2, SDK1), potentially involved in the pathogenesis of HCC. In conclusion, HCC showed a methylation profile completely deregulated and very far from adjacent non-cancerous liver tissues. The SEM analysis provided valuable clues for further investigations in understanding the process of tumorigenesis in HCC.

Original languageEnglish
Pages (from-to)41890-41902
Number of pages13
JournalOncotarget
Volume8
Issue number26
DOIs
Publication statusPublished - 2017

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Epigenomics
Hepatocellular Carcinoma
Mutation
DNA Methylation
Neoplasms
Liver
Virus Diseases
Hepatitis B virus
Hepacivirus
Methylation
Carcinogenesis
Genome

Keywords

  • DNA methylation
  • Epigenetics
  • Genome-wide
  • Hepatocellular carcinoma
  • Stochastic epigenetic mutation

ASJC Scopus subject areas

  • Oncology

Cite this

Epigenome-wide association study in hepatocellular carcinoma : Identification of stochastic epigenetic mutations through an innovative statistical approach. / Gentilini, Davide; Scala, Stefania; Gaudenzi, Germano; Garagnani, Paolo; Capri, Miriam; Cescon, Matteo; Grazi, Gian Luca; Bacalini, Maria Giulia; Pisoni, Serena; Dicitore, Alessandra; Circelli, Luisa; Santagata, Sara; Izzo, Francesco; Di Blasio, Anna Maria; Persani, Luca; Franceschi, Claudio; Vitale, Giovanni.

In: Oncotarget, Vol. 8, No. 26, 2017, p. 41890-41902.

Research output: Contribution to journalArticle

Gentilini, D, Scala, S, Gaudenzi, G, Garagnani, P, Capri, M, Cescon, M, Grazi, GL, Bacalini, MG, Pisoni, S, Dicitore, A, Circelli, L, Santagata, S, Izzo, F, Di Blasio, AM, Persani, L, Franceschi, C & Vitale, G 2017, 'Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach', Oncotarget, vol. 8, no. 26, pp. 41890-41902. https://doi.org/10.18632/oncotarget.17462
Gentilini, Davide ; Scala, Stefania ; Gaudenzi, Germano ; Garagnani, Paolo ; Capri, Miriam ; Cescon, Matteo ; Grazi, Gian Luca ; Bacalini, Maria Giulia ; Pisoni, Serena ; Dicitore, Alessandra ; Circelli, Luisa ; Santagata, Sara ; Izzo, Francesco ; Di Blasio, Anna Maria ; Persani, Luca ; Franceschi, Claudio ; Vitale, Giovanni. / Epigenome-wide association study in hepatocellular carcinoma : Identification of stochastic epigenetic mutations through an innovative statistical approach. In: Oncotarget. 2017 ; Vol. 8, No. 26. pp. 41890-41902.
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