Integrating the Epigenome to Identify Novel Drivers of Hepatocellular Carcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE112221 | GEO | 2018/09/09
REPOSITORIES: GEO
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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.
| S-EPMC6351162 | biostudies-literature
Project description:<p>Despite the growing incidence of hepatocellular carcinoma (HCC) due to increased hepatitis C virus infection and non-alcoholic steatohepatitis in Western populations, the genetic determinants of this cancer have yet to be established. A minority (15-20%) of HCC occurs in livers without cirrhosis or other chronic disease. Because the liver is functionally preserved in these patients and surgical resection of the tumor may be performed safely, and because of the scarcity of livers available for transplantation, non-cirrhotic patients undergo surgical resection for HCC treatment. These resected tumors present investigatory opportunities in two ways: First, they provide tumor specimen which have not been treated with chemotherapy and embolization. Second, the absence of cirrhosis may provide an unconfounded background from which to investigate the genetic tumorigenesis of HCC. In livers with cirrhosis, genetic instability is prevalent as assessed by assays for microsatellite instability, loss of heterozygosity and aberrant DNA methylation. In contrast, in livers without cirrhosis, the non-tumor tissue surrounding HCC have been found to have fewer genetic aberrations. It has been postulated that the pathologic process of cirrhosis may result in the accumulation of many "passenger"; as well as "driver" mutations, and that the examination of the HCC cancer genome may be facilitated in non-cirrhotic livers because of the absence of an accumulated background noise of mutations.</p>
| phs001106 | dbGaP
Project description:Introduction: Hepatocellular carcinoma (HCC) is one of the most aggressive solid tumors and oncogenic pathways (e.g Akt, IGF signaling) are often activated in high proliferating HCC. Among several genetic alterations, epigenetic changes seem to be involved in the development and progression of HCC. DNA hypermethylation of promoter regions is almost always associated with transcriptional silencing and can lead to inactivation of tumor suppressor genes (TSG) in cancer cells. Aim: (1) To identify genes differently methylated in a subclass of HCC associated with proliferation and, (2) To correlate methylation changes with activation of molecular pathways. Methods: gDNA of 20 HCC, 8 cirrhotic and 8 normal liver samples was extracted and the methylation status was detected by the Illumina HumanMethylation27 BeadChip and immunohistochemistry of p-AKT, pIGF IR, p-S6 was analyzed. Results: Unsupervised clustering clearly classified normal livers, cirrhosis and HCC in 3 different groups. 961 genes were significantly hypermethylated in HCC compared to cirrhotic and 3942 genes showed hypermethylation in cirrhotic compared to normal liver tissue. 163 genes showed stepwise significant hypermethylation from normal to cirrhotic to HCC, including well described (p16, SOCS2, SFRP5, RBP1) and potential (SRD5A2, PCDH8, IGF-1R, UCHL1) TSGs, and the miR-10a. 133 genes were specifically hypermethylated in HCC. Among them the transcription factors GATA2, DLX1, and KLF14, all significantly inversely correlated to gene expression (p=0.003, p=0.03, and p=0.007, respectively). The methylation status of SOCS2 (p=0.025) and DLX1 (p=0.025) was significantly correlated to phosphorylation of IGFR1. Samples with RBP1 hypermethylation showed significantly higher AFP serum levels (p=0.018). Conclusion: Whole genome methylation analysis markedly classifies normal, cirrhotic and HCC samples. 8 TSGs play a key role in this stepwise progression of hypermethylation in the development of HCC and could be a promising point of action in anticancer therapy. Genomic DNA extracted from fresh frozen tissue specimens and cell lines was hybridized to genome-wide mthylation beadarray after bisulphite treatment. Keywords: DNA methylation, hepatocellular carcinoma, tissue, cell line
2013-09-27 | E-GEOD-44970 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) affects millions of people worldwide and is a lethal malignancy for which there are no effective therapies. To identify prognostic gene markers for liver cancer, we conducted transcriptome profiling of frozen tissues (tumor and non-tumor) from 300 early-to-advanced stage HCCs plus 40 cirrhotic and 6 normal livers. We have profiles 268 HCC tumor, 243 adjacent non-tumor, 40 cirrhotic and 6 healthy liver samples.
2011-07-05 | E-GEOD-25097 | biostudies-arrayexpress
Project description:Introduction: Hepatocellular carcinoma (HCC) is one of the most aggressive solid tumors and oncogenic pathways (e.g Akt, IGF signaling) are often activated in high proliferating HCC. Among several genetic alterations, epigenetic changes seem to be involved in the development and progression of HCC. DNA hypermethylation of promoter regions is almost always associated with transcriptional silencing and can lead to inactivation of tumor suppressor genes (TSG) in cancer cells. Aim: (1) To identify genes differently methylated in a subclass of HCC associated with proliferation and, (2) To correlate methylation changes with activation of molecular pathways. Methods: gDNA of 20 HCC, 8 cirrhotic and 8 normal liver samples was extracted and the methylation status was detected by the Illumina HumanMethylation27 BeadChip and immunohistochemistry of p-AKT, pIGF IR, p-S6 was analyzed. Results: Unsupervised clustering clearly classified normal livers, cirrhosis and HCC in 3 different groups. 961 genes were significantly hypermethylated in HCC compared to cirrhotic and 3942 genes showed hypermethylation in cirrhotic compared to normal liver tissue. 163 genes showed stepwise significant hypermethylation from normal to cirrhotic to HCC, including well described (p16, SOCS2, SFRP5, RBP1) and potential (SRD5A2, PCDH8, IGF-1R, UCHL1) TSGs, and the miR-10a. 133 genes were specifically hypermethylated in HCC. Among them the transcription factors GATA2, DLX1, and KLF14, all significantly inversely correlated to gene expression (p=0.003, p=0.03, and p=0.007, respectively). The methylation status of SOCS2 (p=0.025) and DLX1 (p=0.025) was significantly correlated to phosphorylation of IGFR1. Samples with RBP1 hypermethylation showed significantly higher AFP serum levels (p=0.018). Conclusion: Whole genome methylation analysis markedly classifies normal, cirrhotic and HCC samples. 8 TSGs play a key role in this stepwise progression of hypermethylation in the development of HCC and could be a promising point of action in anticancer therapy.
2013-09-27 | GSE44970 | GEO
Project description:A Cartes d'Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net) | Affymetrix HG-U133 Plus 2.0 : 5 mixed fibrolamellar carcinoma (m-FLC), 17 pure fibrolamellar carcinoma (p-FLC), 7 hepatocelluar carcinoma arising in non-cirrhotic liver (nc-HCC) and 10 non-tumoral livers (NL).
2014-08-15 | E-MTAB-1503 | biostudies-arrayexpress
Project description:Characterizing the metabolic changes pertaining to hepatocellular carcinoma (HCC) in patients with liver cirrhosis is believed to contribute towards early detection, treatment, and understanding of the molecular mechanisms of HCC. In this study, we compare metabolite levels in sera of 78 HCC cases with 184 cirrhotic controls by using ultra performance liquid chromatography coupled with a hybrid quadrupole time-of-flight mass spectrometry (UPLC-QTOF MS). Following data preprocessing, the most relevant ions in distinguishing HCC cases from patients with cirrhosis are selected by parametric and non-parametric statistical methods. Putative metabolite identifications for these ions are obtained through mass-based database search. Verification of the identities of selected metabolites is conducted by comparing their MS/MS fragmentation patterns and retention time with those from authentic compounds. Quantitation of these metabolites is performed in a subset of the serum samples (10 HCC and 10 cirrhosis) using isotope dilution by selected reaction monitoring (SRM) on triple quadrupole linear ion trap (QqQLIT) and triple quadrupole (QqQ) mass spectrometers. The results of this analysis confirm that metabolites involved in sphingolipid metabolism and phospholipid catabolism such as sphingosine-1-phosphate (S-1-P) and lysophosphatidylcholine (lysoPC 17:0) are up-regulated in sera of HCC vs. those with liver cirrhosis. Down-regulated metabolites include those involved in bile acid biosynthesis (specifically cholesterol metabolism) such as glycochenodeoxycholic acid 3-sulfate (3-sulfo-GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), taurocholic acid (TCA), and taurochenodeoxycholate (TCDCA). These results provide useful insights into HCC biomarker discovery utilizing metabolomics as an efficient and cost-effective platform. Our work shows that metabolomic profiling is a promising tool to identify candidate metabolic biomarkers for early detection of HCC cases in high risk population of cirrhotic patients.
2013-06-30 | MTBLS17 | MetaboLights
Project description:Six frozen hepatocellular carcinoma (HCC) samples (three without cirrhotic and three with cirrhotic background) were selected to analyze the circRNA expression profile through circRNA-seq. A total of 20334 circRNAs were identified in these tumor tissues, which were widely distributed in all chromosomes. Differential analysis revealed that 393 were significantly dysregulated in non-cirrhotic HCC when compared with cirrhotic HCC tissues (log2(fold change) > 1 and p < 0.05). Our study undoubtedly provide a new insight in investigating the initiation of HCC.
2022-05-10 | GSE193862 | GEO
Project description:Hepatocellular carcinoma (HCC) affects millions of people worldwide and is a lethal malignancy for which there are no effective therapies. To identify prognostic gene markers for liver cancer, we conducted transcriptome profiling of frozen tissues (tumor and non-tumor) from 300 early-to-advanced stage HCCs plus 40 cirrhotic and 6 normal livers.
2011-07-05 | GSE25097 | GEO
Project description:Integrating the Epigenome to Identify Novel Drivers of Hepatocellular Carcinoma
| PRJNA445291 | ENA