Comprehensive analysis of transcriptome and metabolome in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma
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ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Liver
DISEASE(S): Cancer
PROVIDER: ST000230 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC_NT and HCC_NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC_NT, HCC, and HCC_NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor, and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC.
| S-EPMC4633735 | biostudies-literature
Project description: Not available
| ST000231 | MetabolomicsWorkbench
Project description:Recurrent non-medullary thyroid carcinoma (NMTC) is a rare disease. We initially characterized 27 recurrent NMTC: 13 papillary thyroid cancers (PTC), 10 oncocytic follicular carcinomas (FTC-OV), and 4 non-oncocytic follicular carcinomas (FTC). A validation cohort composed of benign and malignant (both recurrent and non-recurrent) thyroid tumours was subsequently analysed (n = 20). Methods Data from genome-wide SNP arrays and flow cytometry were combined to determine the chromosomal dosage (allelic state) in these tumours, including mutation analysis of components of PIK3CA/AKT and MAPK pathways. Results All FTC-OVs showed a very distinct pattern of genomic alterations. Ten out of 10 FTC-OV cases showed near-haploidisation with or without subsequent genome endoreduplication. Near-haploidisation was seen in 5/10 as extensive chromosome-wide monosomy (allelic state [A]) with near-haploid DNA indices and retention of especially chromosome 7 (seen as a heterozygous allelic state [AB]). In the remaining 5/10 chromosomal allelic states AA with near diploid DNA indices were seen with allelic state AABB of chromosome 7, suggesting endoreduplication after preceding haploidisation. The latter was supported by the presence of both near-haploid and endoreduplicated tumour fractions in some of the cases. Results were confirmed using FISH analysis. Relatively to FTC-OV limited numbers of genomic alterations were identified in other types of recurrent NMTC studied, except for chromosome 22q which showed alterations in 6 of 13 PTCs. Only two HRAS, but no mutations of EGFR or BRAF were found in FTC-OV. The validation cohort showed two additional tumours with the distinct pattern of genomic alterations (both with oncocytic features and recurrent). Conclusions We demonstrate that recurrent FTC-OV is frequently characterised by genome-wide DNA haploidisation, heterozygous retention of chromosome 7, and endoreduplication of a near-haploid genome. Whether normal gene dosage on especially chromosome 7 (containing EGFR, BRAF, cMET) is crucial for FTC-OV tumour survival is an important topic for future research. 28 thyroid tumors from 27 patients were profiled by SNP array. Comparisons between different types were made.
2012-08-29 | E-GEOD-31828 | biostudies-arrayexpress
Project description:Cancer-associated fibroblasts (CAFs) have been recognized as important contributors to cancer development and progression. However, opposing evidence has been published whether CAFs, in addition to epigenetic, also undergo somatic genetic alterations and whether these changes contribute to carcinogenesis and tumour progression. We combined multiparameter DNA flow cytometry, flow-sorting and 6K SNP-arrays to study DNA aneuploidy, % S-phase, loss of heterozygosity (LOH) and copy number alterations (CNAs) to study somatic genetic alterations in cervical cancer-associated stromal cell fractions (n = 58) from formalin-fixed, paraffin-embedded (FFPE) samples. Tissue sections were examined for the presence of CAFs. Microsatellite analysis was used to study LOH. By flow cytometry we found no proof for DNA aneuploidy in the vimentin-positive stromal cell fractions of any samples (CV G0G1 population 3.7% +/- 1.2; S-phase 1.4% +/- 1.8). The genotype concordance between the stromal cells and the paired normal endometrium samples was > 99.9%. No evidence for CNAs or LOH was found in the stromal cell fractions. In contrast, high frequencies of DNA content abnormalities (43/57), a significant higher S-phase (14.6% +/- 8.5)(p = 0.0001) and substantial numbers of CNAs and LOH were identified in the keratin-positive epithelial cell fractions (CV G0G1 population 4.1% +/- 1.0). Smooth muscle actin and vimentin immunohistochemistry verified the presence of CAFs in all cases tested. LOH hot-spots on chromosomes 3p, 4p and 6p were confirmed by microsatellite analysis but the stromal cell fractions showed retention of heterozygosity only. From our study we conclude that stromal cell fractions from cervical carcinomas are DNA diploid, have a genotype undistinguishable from patient-matched normal tissue and are genetically stable. Stromal genetic changes do not seem to play a role during cervical carcinogenesis and progression. In addition, the stromal cell fraction of cervical carcinomas can be used as reference allowing large retrospective studies of archival FFPE tissues for which no normal reference tissue is available. Paired experiment, Endometrial (non-tumor) cells vs stromal cells from cervical tumors. Biological replicates: 58 patients. From 5 tumors also the tumor fraction was profiled.
2011-11-08 | E-GEOD-29143 | biostudies-arrayexpress
Project description:BackgroundHepatocellular carcinoma is the second most deadly cancer with late presentation and limited treatment options, highlighting an urgent need to better understand HCC to facilitate the identification of early-stage biomarkers and uncover therapeutic targets for the development of novel therapies for HCC.MethodsDeep transcriptome sequencing of tumor and paired non-tumor liver tissues was performed to comprehensively evaluate the profiles of both the host and HBV transcripts in HCC patients. Differential gene expression patterns and the dys-regulated genes associated with clinical outcomes were analyzed. Somatic mutations were identified from the sequencing data and the deleterious mutations were predicted. Lastly, human-HBV chimeric transcripts were identified, and their distribution, potential function and expression association were analyzed.ResultsExpression profiling identified the significantly upregulated TP73 as a nodal molecule modulating expression of apoptotic genes. Approximately 2.5% of dysregulated genes significantly correlated with HCC clinical characteristics. Of the 110 identified genes, those involved in post-translational modification, cell division and/or transcriptional regulation were upregulated, while those involved in redox reactions were downregulated in tumors of patients with poor prognosis. Mutation signature analysis identified that somatic mutations in HCC tumors were mainly non-synonymous, frequently affecting genes in the micro-environment and cancer pathways. Recurrent mutations occur mainly in ribosomal genes. The most frequently mutated genes were generally associated with a poorer clinical prognosis. Lastly, transcriptome sequencing suggest that HBV replication in the tumors of HCC patients is rare. HBV-human fusion transcripts are a common observation, with favored HBV and host insertion sites being the HBx C-terminus and gene introns (in tumors) and introns/intergenic-regions (in non-tumors), respectively. HBV-fused genes in tumors were mainly involved in RNA binding while those in non-tumors tissues varied widely. These observations suggest that while HBV may integrate randomly during chronic infection, selective expression of functional chimeric transcripts may occur during tumorigenesis.ConclusionsTranscriptome sequencing of HCC patients reveals key cancer molecules and clinically relevant pathways deregulated/mutated in HCC patients and suggests that while HBV may integrate randomly during chronic infection, selective expression of functional chimeric transcripts likely occur during the process of tumorigenesis.
| S-EPMC6701074 | biostudies-literature
Project description:BackgroundDNA polymerase delta 1 catalytic subunit (POLD1) plays a key role in DNA replication and damage repair. A defective DNA proofreading function caused by POLD1 mutation contributes to carcinogenesis, while POLD1 overexpression predicts poor prognosis in cancers. However, the effect of POLD1 in hepatocellular carcinoma (HCC) is not well-understood.MethodsExpression patterns of POLD1 were evaluated in TCGA and the HPA databases. Kaplan-Meier curves and Cox regression were used to examine the prognostic value of POLD1. The prognostic and predictive value of POLD1 was further validated by another independent cohort from ICGC database. The influences of DNA copy number variation, methylation and miRNA on POLD1 mRNA expression were examined. The correlation between infiltrating immune cells and POLD1 expression was analyzed. GO and KEGG enrichment analyses were performed to detect biological pathways associated with POLD1 expression in HCC.ResultsPOLD1 was overexpressed in HCC (n = 369) compared with adjacent normal liver (n = 50). POLD1 upregulation was significantly correlated with positive serum AFP and advanced TNM stage. Kaplan-Meier and multivariate analyses suggested that POLD1 overexpression predicts poor prognosis in HCC. DNA copy gain, low POLD1 methylation, and miR‑139-3p downregulation were associated with POLD1 overexpression. Besides, POLD1 expression was associated with the infiltration levels of dendritic cell, macrophage, B cell, and CD4 + T cell in HCC. Functional enrichment analysis suggested "DNA replication", "mismatch repair" and "cell cycle" pathways might be involved in the effect of POLD1 on HCC pathogenesis. Additionally, POLD1 mRNA expression was significantly associated with tumor mutation burden, microsatellite instability, and prognosis in various tumors.ConclusionsPOLD1 may be a potential prognostic marker and promising therapeutic target in HCC.
| S-EPMC8862270 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the leading cause of cancer-associated death in the world. However, due to the complexity of HCC, it is urgent for us to find a reliable and accurate biomarker for HCC gene therapy.TopBP1-interacting checkpoint and replication regulator (TICRR), known as Treslin in vertebrate and sld3 in yeast, is involved in the tumorigenesis, progression, matastasis, diagnosis, and predicting prognosis of HCC. Disappointingly, the mechanism of TICRR expression in HCC is still not described in detail and requires further analysis. In this study, TCGA ( www.tcga-data.nci.nih.gov/tcga/ ) datasets and GEO ( www.ncbi.nlm.nih.gov/geo ) datasets were used to analyze the expression of TICRR in HCC, the relevance of TICRR mRNA expression and clinicopathological characteristics in patients with HCC, and the relationship between TICRR expression and immune infiltration level in Patients with HCC. Based on MethSurv database, the impact of TICRR in patients with HCC was investigated. In addition, GO/KEGG enrichment analysis of TICRR co-expression was performed using the R package. TICRR was found drastically highly expressed in a variety of cancer types including HCC.ROC curve analysis showed that TICRR had higher accuracy in predicting HCC compared with AFP. The expression level of TICRR was marked positively correlated with tumor stage and prognosis in Patients with HCC.GO/KEGG enrichment analysis showed that TICRR was associated with cell division and cell cycle as well as p53 signaling pathway. In addition, patients with high TICRR methylation of cg05841809, cg09403165, and cg03312532 CpG sites were significantly correlated with poor prognosis of HCC. This study demonstrated that increased TICRR expression in HCC might play an important role in the tumorigenesis, progression, diagnosis, and predicting prognosis of HCC. Therefore, TICRR might be used as a promising diagnostic and prognostic biomarker for HCC gene therapy.
| S-EPMC10902024 | biostudies-literature
Project description:MicroRNAs are important negative regulators of protein coding gene expression, and have been studied intensively over the last few years. To this purpose, different measurement platforms to determine their RNA abundance levels in biological samples have been developed. In this study, we have systematically compared 12 commercially available microRNA expression platforms by measuring an identical set of 20 standardized positive and negative control samples, including human universal reference RNA, human brain RNA and titrations thereof, human serum samples, and synthetic spikes from homologous microRNA family members. We developed novel quality metrics in order to objectively assess platform performance of very different technologies such as small RNA sequencing, RT-qPCR and (microarray) hybridization. We assessed reproducibility, sensitivity, quantitative performance, and specificity. The results indicate that each method has its strengths and weaknesses, which helps guiding informed selection of a quantitative microRNA gene expression platform in function of particular study goals.
2013-09-01 | E-MTAB-1815 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide. With a rising rate, it is a prominent source of mortality. Patients with advanced fibrosis, predominantly cirrhosis and hepatitis B are predisposed to developing HCC. Individuals with chronic hepatitis B and C infections are most commonly afflicted. Different therapeutic options, including liver resection, transplantation, systemic and local therapy, must be tailored to each patient. Liver transplantation offers leading results to achieve a cure. The Milan criteria is acknowledged as the model to classify the individuals that meet requirements to undergo transplantation. Mean survival remains suboptimal because of long waiting times and limited donor organ resources. Recent debates involve expansion of these criteria to create options for patients with HCC to increase overall survival.
| S-EPMC4651909 | biostudies-literature
Project description:IntroductionHepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Despite the therapeutic advances in HCC in the past few decades, the mortality rate of HCC is still high. Hepatitis C (HCV) infection is one of the major etiological risk factors of HCCs. However, the underlying mechanisms of HCV-induced hepatocarcinogenesis remain largely unclear.Material and methodsOur study represented the comprehensive analysis of differentially expressed lncRNAs in HCV-positive HCC for the first time by analyzing the public dataset GSE17856. Co-expression network and gene ontology (GO) analysis revealed the functions of those differentially expressed lncRNAs.ResultsWe identified 256 upregulated lncRNAs and 198 downregulated lncRNAs in HCV- positive HCC compared to the normal liver tissues. Co-expression network and GO analysis showed that these lncRNAs were involved in regulating metabolism, energy pathways, proliferation and the immune response. Seven lncRNAs (LOC341056, CCT6P1, PTTG3P, LOC643387, LOC100133920, C3P1 and C22orf45) were identified as key lncRNAs and co-expressed with more than 100 differentially expressed genes (DEGs) in HCV-related HCC. Kaplan-Meier analysis showed that higher expression levels of LOC643387, PTTG3P, LOC341056, CCT6P1 and lower expression levels of C3P1 and C22orf45 were associated with shorter survival time in the TCGA dataset.ConclusionsWe believe that this study can provide novel potential therapeutic and prognostic biomarkers for HCV-positive HCC.
| S-EPMC7811325 | biostudies-literature