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Integrating the Epigenome to Identify Novel Drivers of Hepatocellular Carcinoma

ABSTRACT: Integrating the Epigenome to Identify Novel Drivers of Hepatocellular Carcinoma

PROVIDER: PRJNA445291 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6880460_1.fastq.gz	Fastqsanger.gz
	SRR6880460_2.fastq.gz	Fastqsanger.gz
	SRR6880470_1.fastq.gz	Fastqsanger.gz
	SRR6880470_2.fastq.gz	Fastqsanger.gz
	SRR6880480_1.fastq.gz	Fastqsanger.gz

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Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma.

Project description:Disruption of epigenetic mechanisms has been intimately linked to the etiology of human cancer. Understanding how these epigenetic mechanisms (including DNA methylation [5mC], hydroxymethylation [5hmC], and histone post-translational modifications) work in concert to drive cancer initiation and progression remains unknown. Hepatocellular carcinoma (HCC) is increasing in frequency in Western countries but lacks efficacious treatments. The epigenome of HCC remains understudied. To better understand the epigenetic underpinnings of HCC, we performed a genome-wide assessment of 5mC, 5hmC, four histone modifications linked to promoter/enhancer function (H3K4me1, H3K27ac, H3K4me3, and H3K27me3), and transcription across normal, cirrhotic, and HCC liver tissue. Implementation of bioinformatic strategies integrated these epigenetic marks with each other and with transcription to provide a comprehensive epigenetic profile of how and when the liver epigenome is perturbed during progression to HCC. Our data demonstrate significant deregulation of epigenetic regulators combined with disruptions in the epigenome hallmarked by profound loss of 5hmC, locus-specific gains in 5mC and 5hmC, and markedly altered histone modification profiles, particularly remodeling of enhancers. Data integration demonstrates that these marks collaborate to influence transcription (e.g., hyper-5hmC in HCC-gained active enhancers is linked to elevated expression) of genes regulating HCC proliferation. Two such putative epigenetic driver loci identified through our integrative approach, COMT and FMO3, increase apoptosis and decrease cell viability in liver-derived cancer cell lines when ectopically re-expressed. Conclusion: Altogether, integration of multiple epigenetic parameters is a powerful tool for identifying epigenetically regulated drivers of HCC and elucidating how epigenome deregulation contributes to liver disease and HCC.

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Integrating the Epigenome to Identify Novel Drivers of Hepatocellular Carcinoma

Project description:Gene expression, histone modification, DNA methylation, and DNA hydroxymethylation from normal, cirrhotic, and HCC livers

2018-09-09 | GSE112221 | GEO

Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma [tumor]

Project description:Cancer is a genetic disease with frequent somatic alterations in DNA. Study of recurrent copy number aberrations (CNAs) in human cancers would enable the elucidation of disease mechanisms and the identification of key oncogenic drivers with causal roles in oncogenesis. We have comprehensively and systematically characterized CNAs and accompanied gene expression changes in the tumors and their matched non-tumor liver tissues from 286 hepatocellular carcinoma (HCC) patients. Our analysis identified 29 recurrently amplified regions and 22 deleted regions with a high level of copy number changes, harboring established oncogenes and tumor suppressors, including CCND1, MET, CDKN2A and CDKN2B, as well as many other genes not previously reported to be involved in liver carcinogenesis. Cis-acting genes in the amplification and deletion peaks were enriched in core cancer pathways, including cell cycle, p53, PI3K, MAPK, Wnt and TGFβ signaling in large proportions of HCCs. We further validated two candidate driver genes, BCL9 and MTDH, from the recurrent focal amplification peaks and showed that they play a significant role in HCC growth and survival. In summary, we have demonstrated that characterizing the CNA landscape in HCC will facilitate the understanding of disease mechanisms and the identification of oncogenic drivers that may serve as potential therapeutic targets for the treatment of this devastating disease. Two hundred and eighty-six hepatocellular carcinoma tumors and their matched non-tumor adjacent liver tissue samples were genotyped using Illumina HumanOmni1-Quad BeadChip to estimate their somatic copy number profiles.

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Project description:Cancer is a genetic disease with frequent somatic alterations in DNA. Study of recurrent copy number aberrations (CNAs) in human cancers would enable the elucidation of disease mechanisms and the identification of key oncogenic drivers with causal roles in oncogenesis. We have comprehensively and systematically characterized CNAs and accompanied gene expression changes in the tumors and their matched non-tumor liver tissues from 286 hepatocellular carcinoma (HCC) patients. Our analysis identified 29 recurrently amplified regions and 22 deleted regions with a high level of copy number changes, harboring established oncogenes and tumor suppressors, including CCND1, MET, CDKN2A and CDKN2B, as well as many other genes not previously reported to be involved in liver carcinogenesis. Cis-acting genes in the amplification and deletion peaks were enriched in core cancer pathways, including cell cycle, p53, PI3K, MAPK, Wnt and TGFβ signaling in large proportions of HCCs. We further validated two candidate driver genes, BCL9 and MTDH, from the recurrent focal amplification peaks and showed that they play a significant role in HCC growth and survival. In summary, we have demonstrated that characterizing the CNA landscape in HCC will facilitate the understanding of disease mechanisms and the identification of oncogenic drivers that may serve as potential therapeutic targets for the treatment of this devastating disease. Thirty hepatocellular carcinoma cell lines were genotyped using Illumina HumanOmni1-Quad BeadChip to estimate their copy number profiles relative to pooled Hapmap samples.

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Deep targeted sequencing of multiregional sampling in hepatocellular carcinoma

Project description:The purpose of this experiment of high-coverage DNA sequencing of 58 frequently mutated genes in hepatocellular carcinoma (HCC) is to confirm clonal distribution of the known HCC drivers in samples corresponding to multiple regions of a tumor.

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Integrating the Epigenome and Transcriptome of Hepatocellular Carcinoma to Identify Systematic Enhancer Aberrations and Establish an Aberrant Enhancer-Related Prognostic Signature.

Project description:Recently, emerging evidence has indicated that aberrant enhancers, especially super-enhancers, play pivotal roles in the transcriptional reprogramming of multiple cancers, including hepatocellular carcinoma (HCC). In this study, we performed integrative analyses of ChIP-seq, RNA-seq, and whole-genome bisulfite sequencing (WGBS) data to identify intergenic differentially expressed enhancers (DEEs) and genic differentially methylated enhancers (DMEs), along with their associated differentially expressed genes (DEE/DME-DEGs), both of which were also identified in independent cohorts and further confirmed by HiC data. Functional enrichment and prognostic model construction were conducted to explore the functions and clinical significance of the identified enhancer aberrations. We identified a total of 2,051 aberrant enhancer-associated DEGs (AE-DEGs), which were highly concurrent in multiple HCC datasets. The enrichment results indicated the significant overrepresentations of crucial biological processes and pathways implicated in cancer among these AE-DEGs. A six AE-DEG-based prognostic signature, whose ability to predict the overall survival of HCC was superior to that of both clinical phenotypes and previously published similar prognostic signatures, was established and validated in TCGA-LIHC and ICGC-LIRI cohorts, respectively. In summary, our integrative analysis depicted a landscape of aberrant enhancers and associated transcriptional dysregulation in HCC and established an aberrant enhancer-derived prognostic signature with excellent predictive accuracy, which might be beneficial for the future development of epigenetic therapy for HCC.

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