Universität zu Köln

Czauderna, Carolin, Poplawski, Alicia, O'Rourke, Colm J., Castven, Darko, Perez-Aguilar, Benjamin, Becker, Diana, Heilmann-Heimbach, Stephanie, Odenthal, Margarete ORCID: 0000-0002-2424-0960, Amer, Wafa, Schmiel, Marcel, Drebber, Uta, Binder, Harald, Ridder, Dirk A., Schindeldecker, Mario ORCID: 0000-0003-4843-7992, Straub, Beate K., Galle, Peter R., Andersen, Jesper B., Thorgeirsson, Snorri S., Park, Young Nyun and Marquardt, Jens U. (2021). Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis. JCI Insight, 6 (17). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

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Abstract

Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n = 7), low-(n = 4) and high-grade (n = 9) dysplastic lesions, and early (n = 5) and progressed (n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further employed for clonality analyses, indicating multiclonal origin in the majority of investigated HCCs. Alterations in DNA methylation progressively increased from liver cirrhosis (CL) to dysplastic lesions and reached a maximum in early HCCs. Associated early alterations identified by Ingenuity Pathway Analysis (IPA) involved apoptosis, immune regulation, and stemness pathways, while late changes centered on cell survival, proliferation, and invasion. We further validated 23 putative epidrivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated, and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines. Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for potentially novel therapeutic approaches.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Czauderna, Carolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Poplawski, Alicia UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Rourke, Colm J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Castven, Darko UNSPECIFIED UNSPECIFIED UNSPECIFIED Perez-Aguilar, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Heilmann-Heimbach, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED orcid.org/0000-0002-2424-0960 UNSPECIFIED Amer, Wafa UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmiel, Marcel UNSPECIFIED UNSPECIFIED UNSPECIFIED Drebber, Uta UNSPECIFIED UNSPECIFIED UNSPECIFIED Binder, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Ridder, Dirk A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schindeldecker, Mario UNSPECIFIED orcid.org/0000-0003-4843-7992 UNSPECIFIED Straub, Beate K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Galle, Peter R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Andersen, Jesper B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thorgeirsson, Snorri S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Park, Young Nyun UNSPECIFIED UNSPECIFIED UNSPECIFIED Marquardt, Jens U. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-599752
DOI:	10.1172/jci.insight.146196
Journal or Publication Title:	JCI Insight
Volume:	6
Number:	17
Date:	2021
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	2379-3708
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEPATOCELLULAR-CARCINOMA; DNA METHYLATION; GENE-EXPRESSION; RECURRENCE; CLASSIFICATION; PROGNOSIS; ORIGIN Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59975