GeneSetDB: A comprehensive meta‐database, statistical and visualisation framework for gene set analysis

Araki, Hiromitsu; Knapp, Christoph; Tsai, Peter; Print, Cristin G.

doi:10.1016/j.fob.2012.04.003

Cited by 70 publications

(71 citation statements)

References 46 publications

(35 reference statements)

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“…To gain insight into the biological function of CIS genes, we used the Ingenuity Pathway Analysis (IPA), Database for Annotation, Visualization and Integrated Discovery (DAVID) 64 , Kyoto Encyclopedia of Genes and Genomes (KEGG) 65 and GeneSetDB 66 analysis platforms. We found significant enrichment of CIS genes in many cancer-related signaling pathways and biological processes, including Wnt/β-catenin, transforming growth factor (TGF)-β, phosphoinositide 3-kinase (PI3K) and MAPK signaling and biological processes regulating ubiquitin-mediated proteolysis, tight junctions, the cell cycle and axonal guidance (Supplementary Table 17a,b).…”

Section: Resultsmentioning

confidence: 99%

“…This database contains directional (for example, transcription factor → DNA target, kinase → protein substrate) and non-directional (for example, protein-protein binding) molecular links. Data on molecular links were sourced from GeneSetDB 66 supplemented by molecular links manually identified from the literature and accessed from the online databases MetaCore (Thomson Reuters), IPA (Qiagen) and TRANSFAC 93 . Pairs of CIS genes found in the virtual database were visualized using the Cytoscape environment 94 .…”

Section: Methodsmentioning

confidence: 99%

“…We downloaded 4,076 gene sets from GeneSetDB 66 with the membership of each gene set indicated by Entrez Gene number. Entrez Gene identifiers were matched to CCGs using the Mouse Genome Informatics (MGI) database (accessed 21 September 2012).…”

Section: Methodsmentioning

confidence: 99%

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Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma

et al. 2015

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Although nearly half of human melanomas harbor oncogenic BRAFV600E mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in BrafV600E mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAFV600E melanoma and discover new genes with potential clinical importance in human melanoma.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma

et al. 2015

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“…Gene ontology/pathway enrichment analyses were carried out using Fatigo software [35], GeneSetDB [36], GATHER (http://gather.genome.duke.edu/) and IPA (Ingenuity systems, http://www.ingenuity.com). …”

Section: Methodsmentioning

confidence: 99%

Vasohibin-1 is identified as a master-regulator of endothelial cell apoptosis using gene network analysis

Affara

Sanders

Araki³

et al. 2013

BMC Genomics

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BackgroundApoptosis is a critical process in endothelial cell (EC) biology and pathology, which has been extensively studied at protein level. Numerous gene expression studies of EC apoptosis have also been performed, however few attempts have been made to use gene expression data to identify the molecular relationships and master regulators that underlie EC apoptosis. Therefore, we sought to understand these relationships by generating a Bayesian gene regulatory network (GRN) model.ResultsECs were induced to undergo apoptosis using serum withdrawal and followed over a time course in triplicate, using microarrays. When generating the GRN, this EC time course data was supplemented by a library of microarray data from EC treated with siRNAs targeting over 350 signalling molecules.The GRN model proposed Vasohibin-1 (VASH1) as one of the candidate master-regulators of EC apoptosis with numerous downstream mRNAs. To evaluate the role played by VASH1 in EC, we used siRNA to reduce the expression of VASH1. Of 10 mRNAs downstream of VASH1 in the GRN that were examined, 7 were significantly up- or down-regulated in the direction predicted by the GRN.Further supporting an important biological role of VASH1 in EC, targeted reduction of VASH1 mRNA abundance conferred resistance to serum withdrawal-induced EC death.ConclusionWe have utilised Bayesian GRN modelling to identify a novel candidate master regulator of EC apoptosis. This study demonstrates how GRN technology can complement traditional methods to hypothesise the regulatory relationships that underlie important biological processes.

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“…An updated Illumina probe set annotation by ReMOAT was used [17]. Gene set analysis was performed using GeneSetDB which is a comprehensive meta-database, statistical, and visualization framework for gene set analysis [18]. An adjusted P value of 0.05 was set to be the level of significant gene sets with the additional requirement of at least three genes of annotated biological functions.…”

Section: Microarray Experiments and Analysismentioning

confidence: 99%

Haptoglobin promoter polymorphism rs5472 as a prognostic biomarker for peptide vaccine efficacy in castration-resistant prostate cancer patients

Araki

Pang

Komatsu

et al. 2015

Cancer Immunol Immunother

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Personalized peptide vaccination (PPV) is an attractive approach to cancer immunotherapy with strong immune-boosting effects conferring significant clinical benefit. However, as with most therapeutic agents, there is a difference in clinical efficacy among patients receiving PPV. Therefore, a useful biomarker is urgently needed for prognosticating clinical outcomes to preselect patients who would benefit the most from PPV. In this retrospective study, to detect a molecular prognosticator of clinical outcomes for PPV, we analyzed whole-genome gene expression profiles of peripheral blood mononuclear cells (PBMCs) in castration-resistant prostate cancer (CRPC) patients before administration of PPV. Cox regression analysis revealed that mRNA expression of myeloperoxidase, haptoglobin, and neutrophil elastase was significantly associated with overall survival (OS) among vaccinated CRPC patients (adjusted P < 0.01). By promoter sequence analysis of these three genes, we found that rs5472 of haptoglobin (HP), an acute-phase plasma glycoprotein, was strongly correlated to OS of vaccinated CRPC patients (P = 0.0047, hazard ratio 0.47; 95 % confidence interval 0.28-0.80). Furthermore, both HP mRNA expression in PBMCs and protein level in plasma of CRPC patients before administration of PPV exhibited rs5472 dependence (P < 0.001 for mRNA expression and P < 0.05 for protein level). Our findings suggest that rs5472 may play an important role in the immune response to PPV via regulation of HP. Thus, we concluded that rs5472 is a potential prognostic biomarker for PPV.

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GeneSetDB: A comprehensive meta‐database, statistical and visualisation framework for gene set analysis

Cited by 70 publications

References 46 publications

Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma

Transposon mutagenesis identifies genetic drivers of BrafV600E melanoma

Vasohibin-1 is identified as a master-regulator of endothelial cell apoptosis using gene network analysis

Haptoglobin promoter polymorphism rs5472 as a prognostic biomarker for peptide vaccine efficacy in castration-resistant prostate cancer patients

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