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.
Highlights
Hepatocellular carcinoma (HCC) is a hallmark of inflammation-induced cancers and ranks among the most common causes of cancer-related deaths worldwide [1]
Integrative transcriptome analysis of dysplastic lesions, early hepatocellular carcinoma (eHCC), and progresses to advanced HCC (pHCC) in patients with chronic HBV infection recently revealed that molecular profiles of early lesions are relatively uniform, whereas a sharp increase in molecular heterogeneity is induced in pHCC [5]
Evidence for the importance of a DNA methylation dependent, multistep sequence of molecular alterations in hepatocarcinogenesis was further demonstrated in HBV-related liver cancers and indicated a major contribution of epigenetics in deregulation of key pro-oncogenic molecules from cirrhotic nodules over dysplastic nodules (DNs) to eHCC and pHCC [16]
Summary
Hepatocellular carcinoma (HCC) is a hallmark of inflammation-induced cancers and ranks among the most common causes of cancer-related deaths worldwide [1]. It is well established that epigenetic mechanisms in cancer cells are highly influenced by microenvironmental stimuli In this context, changes in DNA methylation patterns are believed to be early events in tumor development in inflammatory cancers preceding allelic imbalances and leading to cancer progression, thereby adding considerable complexity to the pathogenesis of liver and other cancers [6, 7]. Evidence for the importance of a DNA methylation dependent, multistep sequence of molecular alterations in hepatocarcinogenesis was further demonstrated in HBV-related liver cancers and indicated a major contribution of epigenetics in deregulation of key pro-oncogenic molecules from cirrhotic nodules over DNs to eHCC and pHCC [16].
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