Dataset Information

Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma.

ABSTRACT: 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.

SUBMITTER: Hlady RA

PROVIDER: S-EPMC6351162 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma.

Hlady Ryan A RA Sathyanarayan Aishwarya A Thompson Joyce J JJ Zhou Dan D Wu Qunfeng Q Pham Kien K Lee Jeong-Heon JH Liu Chen C Robertson Keith D KD

Hepatology (Baltimore, Md.) 20190105 2

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 understan ...[more]

PMID: 30136421

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Project description:BackgroundIncorporating patient reporting of symptomatic adverse events (AEs) is important in evaluating safety and tolerability in cancer clinical trials. The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to assess the frequency, severity, and/or interference of patient-reported symptomatic AEs. The objective of this study was to identify, based on oncologist and patient interviews, a relevant subset of symptomatic AEs from the PRO-CTCAE that can be used to optimize patient reporting of symptomatic AEs in hepatocellular carcinoma (HCC) clinical trials.MethodsQualitative and quantitative data on HCC diagnosis, treatment, symptoms, and side effects were collected from patients. Using a numerical rating scale, medical oncologists specializing in HCC rated the importance of (1) 34 symptomatic AEs (grade ≥ 2) identified in past sponsor HCC clinical trials, (2) each PRO-CTCAE symptomatic AE item to the patient, and (3) each PRO-CTCAE symptomatic AE item with respect to patient safety or tolerability. Patients completed the PRO-CTCAE items and were debriefed on the importance of each PRO-CTCAE symptomatic AE to them.ResultsFive medical oncologists from the United States, Spain, Taiwan, Korea, and Hong Kong with 14 to 30 years of experience, and 17 patients with HCC and Child-Pugh class A or B cirrhosis status completed interviews. Medical oncologists rated the following symptomatic AEs from prior trials as being highly important to patients (mean rating of ≥7 on a scale from 0 to 10): hand-foot syndrome, diarrhea, fatigue, decreased appetite, rash, vomiting, and weight loss. PRO-CTCAE symptomatic AEs rated by medical oncologists as being highly important to patients included diarrhea, vomiting, shivering or shaking chills, hand-foot syndrome, rash, fatigue, difficulty swallowing, decreased appetite, and loss of control of bowel movements. Patients rated the following PRO-CTCAE symptomatic AEs as being highly important: loss of appetite/lack of interest in food, pain/tenderness at injection/insertion site, fatigue/lack of energy/tiredness, nausea, and hair loss.ConclusionsThis study identified a preliminary list of clinically relevant symptomatic AEs from interviews with both medical oncologists and patients that can be used to support assessments of treatment safety and tolerability in HCC clinical trials.

Dataset Information

Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma.

Publications

Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma.

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