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DOI: 10.1055/s-0039-1695307
Sequential (epi)genetic changes during liver cancer development and progression
Publication History
Publication Date:
13 August 2019 (online)
Background:
Development of primary liver cancer is a multi-stage process. Pre-neoplastic dysplastic lesions emerge on the basis of chronic liver damage and evolve into early hepatocellular carcinoma (eHCC) and, subsequently, progressed HCC (pHCC). Detailed molecular characterization of pre-neoplastic lesions at risk for malignant transformation would advance our diagnostic and therapeutic approaches. We here utilized integrative molecular analyses to characterize the sequential evolution of liver cancer and aimed to define key epigenetic Drivers.
Methods:
Methylation 450k-beadchip analyses were performed on cirrhotic liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, eHCC (n = 5) and pHCC (n = 3) from 8 HCC patients with chronic hepatitis B infection. Differentially methylated gene regions (DMGR) were identified in comparison to non-cirrhotic and non-infected liver (n = 9). Potential epi-drivers were identified by integrative analyses of transcriptomic changes and validated in an independent cohort from the TCGA database.
Results:
The proportion of hypermethylated DMGR progressively increased from cirrhosis over dysplastic- to HCC and peaked in eHCC lesions. Early epigenetic alterations involved signaling pathways related to cell death, apoptosis and immune regulation, while late changes centered on cell survival, growth and migration. A common regulation of stem cell-associated pathways including Wnt/b-catenin signaling was revealed in dysplastic as well as eHCC potentially predisposing tumor progression. We further detected changes in the immune composition of dysplastic nodules based on corresponding gene expression profiles. Moreover, we identified 101 genes with significant methylom changes in dysplastic and early cancerous lesions with concomitant progressive gene expression alterations in cancer tissue. We validated our epigenetic marks in cancer tissue using an independent cohort of 362 HCC to surrounding liver samples.
Conclusion:
Our results confirm that epigenetic changes occur early during hepatocarcinogenesis. Epigenetic modifications, therefore, might be of high diagnostic utility for the identification of dysplastic lesions at risk for cancer progression and might provide targets for new effective therapeutic approaches.
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