A Methylation-Based Signature Predicts Survival In Hepatocellular Carcinoma Patient
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Antonio Gómez
PROVIDER: E-GEOD-56588 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:BACKGROUND & AIMS: In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona-Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues. METHODS: We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287) and adjacent nontumor, cirrhotic tissue (n = 226). We evaluated gene expression signatures with reported prognostic ability generated from tumor or cirrhotic tissue in 18 and 4 reports, respectively. In 15 additional patients, we profiled samples from the center and periphery of the tumor, to determine stability of signatures. Data analysis included Cox modeling and random survival forests to identify independent predictors of tumor recurrence. RESULTS: Gene expression signatures that were associated with aggressive HCC were clustered, as well as those associated with tumors of progenitor cell origin and those from nontumor, adjacent, cirrhotic tissues. On multivariate analysis, the tumor-associated signature G3-proliferation (hazard ratio [HR], 1.75; P = .003) and an adjacent poor-survival signature (HR, 1.74; P = .004) were independent predictors of HCC recurrence, along with satellites (HR, 1.66; P = .04). Samples from different sites in the same tumor nodule were reproducibly classified. CONCLUSIONS: We developed a composite prognostic model for HCC recurrence, based on gene expression patterns in tumor and adjacent tissues. These signatures predict early and overall recurrence in patients with HCC, and complement findings from clinical and pathology analyses. Center and peripheral portions of hepatocellular carcinoma tumors as well as surrounding non-tumor cirrhotic liver tissues were obtained from fresh frozen surgically resected tissues, and isolated total RNA samples were analyzed for genome-wide expression profiles.
2014-03-25 | E-GEOD-56140 | 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:The methylation profiles of bisulfite-modified DNA of CD19+ cells from MZ twins discordant for CVID were compared using the Infinium HumanMethylation450 BeadChips (Illumina, Inc., San Diego, CA,). This platform allows the interrogation of >485,000 methylation sites per sample at single-nucleotide resolution, and comprises an average of 17 CpG sites per gene in the 99% of RefSeq genes. 96% of CpG islands are covered, with additional coverage in CpG island shores and the regions flanking them. The samples were hybridized in the array following the manufacturer’s instructions. Total DNA isolated by standard procedures from CD19+ cells (total B lymphocytes) corresponding to two monozygotic twins discordant for common variable immunodeficiency.
2015-06-17 | E-GEOD-63849 | biostudies-arrayexpress
Project description:Epigenetic deregulation is a critical event in human malignancies. A number of DNA methylation markers are currently under evaluation as diagnostic and prognostic biomarkers for many cancers. However, its potential role in hepatocellular carcinoma (HCC) is under-explored. Aims: To develop a DNA methylation-based prognostic signature in surgically resected HCC
2015-02-13 | GSE56588 | GEO
Project description:We examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared to non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis. Bisulfite modification of 1µg DNA was conducted using an EZ DNA Methylation Kit (Zymo Research, Irvine, CA) according to the manufacturer’s procedure. The Infinium Methylation 450K assay was performed according to Illumina’s standard protocol. Six HCC tumor/adjacent non-tumor tissue pairs were processed on the same chip to avoid chip-to-chip variation.
2014-01-30 | E-GEOD-54503 | biostudies-arrayexpress
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:Laser Microdissection (LMD) associated to LC-MS/MS were used to analyze the proteome of neoplastic islands and stroma tumor of Formalin-Fixed and Paraffin Embedded (FFPE) OSCC tissues to identify proteins of prognostic value. Label-free protein quantification and statistical analysis revealed neoplastic islands proteins and from stroma tumor as correlated to clinicopathological data including lymphonode status and recurrence.
2018-09-10 | PXD007232 | Pride
Project description:The remarkable molecular heterogeneity in hepatocellular carcinoma (HCC) continues to challenge development of effective treatments and biomarkers. Here we report that the gene encoding a secreted glycoprotein, ADAMTSL5, is overexpressed and displays hypermethylated CpG islands in its gene body region in a clinically relevant mouse genetic model of HCC as well as in a significant proportion of human HCC patients. Immunohistological analysis of human HCCs revealed strong ADAMTSL5 immunostaining in tumour cells and histiocytes, in contrast to normal liver. Functional targeting of ADAMTSL5 in oncogenesis using shRNA interfered with tumorigenic properties of HCC cells both in vitro and in vivo. Furthermore, ADAMTSL5 overexpression conferred tumorigenic capability to genetically sensitized, non-transformed hepatocytes in nude mice. Mechanistically, ADAMTSL5 abrogation led to reduction of several oncogenic inputs, including the receptor tyrosine kinases MET, EGFR, PDGFRβ, IGF1Rβ, and FGFR4, suggesting it as a master regulator of HCC tumorigenicity when overexpressed.
2020-11-17 | PXD016634 | Pride
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:Aberrant DNA hypermethylation of CpG islands occurs frequently throughout the genome in human colorectal cancer (CRC). A genome-scale DNA hypermethylation analysis technique using plasma is attractive for the noninvasive early detection of CRC. The methylated CpG tandems amplification and sequencing (MCTA-Seq) method was applied to plasma samples from 147 CRC patients and 134 controls in which 5 from the CRC patients and 2 from the control subjects failed to pass a quality control value and were excluded from further analysis. The capacity of the method for discriminating CRC and hepatocellular carcinoma (HCC) was assessed. We identified many DNA methylation markers including known (e.g., SEPT9 and IKZF1) and novel (e.g., EMBP1, KCNQ5 and CHST11) CpG islands for detecting CRC in blood. A panel of 80 markers significantly discriminated early stage CRC and controls with a sensitivity of 78% and a specificity of 90%. This method can efficiently distinguish between early stage CRC and HCC. MCTA-Seq is a promising method for the noninvasive detection of CRC that also shows great potential for identifying the tissue of origin of cancer.
2019-05-31 | GSE124600 | GEO