Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach
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Davide Gentilini1, Stefania Scala2, Germano Gaudenzi3, Paolo Garagnani4,5, Miriam Capri4,5, Matteo Cescon6, Gian Luca Grazi7, Maria Giulia Bacalini8, Serena Pisoni1, Alessandra Dicitore1, Luisa Circelli9, Sara Santagata2, Francesco Izzo10, Anna Maria Di Blasio1, Luca Persani1,3, Claudio Franceschi4,5,8 and Giovanni Vitale1,3
1Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, Italy
2Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS Fondazione “G. Pascale”, Napoli, Italy
3Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy
4Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna, Bologna, Italy
5Interdepartmental Center "L. Galvani", University of Bologna, Bologna, Italy
6DIMEC-Department of General Surgery and Medicine Sciences, S. Orsola-Malpighi Hospital, Bologna, Italy.
7Regina Elena National Cancer Institute Via Elio Chianesi 53, Rome, Italy
8IRCCS Institute of Neurological Sciences, Bologna, Italy
9Department of Experimental Oncology, Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, Napoli, Italy
10Department of Surgical Oncology, Abdominal and Hepatobiliary Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS Fondazione “ G. Pascale”, Napoli, Italy
Giovanni Vitale, email: [email protected]
Keywords: hepatocellular carcinoma, stochastic epigenetic mutation, epigenetics, DNA methylation, genome-wide
Received: January 27, 2017 Accepted: April 15, 2017 Published: April 27, 2017
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.
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