An Integrative Genomic and Transcriptomic Analysis Reveals Potential Targets Associated with Cell Proliferation in Uterine Leiomyomas

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dc.contributor.authorDa Cirilo, Priscilaniele Ramos [UNESP]
dc.contributor.authorMarchi, Fábio Albuquerque
dc.contributor.authorde Barros Filho, Mateus Camargo
dc.contributor.authorRocha, Rafael Malagoli
dc.contributor.authorDomingues, Maria Aparecida Custódio [UNESP]
dc.contributor.authorJurisica, Igor
dc.contributor.authorPontes, Anaglória [UNESP]
dc.contributor.authorRogatto, Silvia Regina [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionFundação Antonio Prudente, São Paulo
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversity Health Network
dc.date.accessioned2014-05-27T11:28:38Z
dc.date.available2014-05-27T11:28:38Z
dc.date.issued2013-03-04
dc.description.abstractBackground: Uterine Leiomyomas (ULs) are the most common benign tumours affecting women of reproductive age. ULs represent a major problem in public health, as they are the main indication for hysterectomy. Approximately 40-50% of ULs have non-random cytogenetic abnormalities, and half of ULs may have copy number alterations (CNAs). Gene expression microarrays studies have demonstrated that cell proliferation genes act in response to growth factors and steroids. However, only a few genes mapping to CNAs regions were found to be associated with ULs. Methodology: We applied an integrative analysis using genomic and transcriptomic data to identify the pathways and molecular markers associated with ULs. Fifty-one fresh frozen specimens were evaluated by array CGH (JISTIC) and gene expression microarrays (SAM). The CONEXIC algorithm was applied to integrate the data. Principal Findings: The integrated analysis identified the top 30 significant genes (P<0.01), which comprised genes associated with cancer, whereas the protein-protein interaction analysis indicated a strong association between FANCA and BRCA1. Functional in silico analysis revealed target molecules for drugs involved in cell proliferation, including FGFR1 and IGFBP5. Transcriptional and protein analyses showed that FGFR1 (P = 0.006 and P<0.01, respectively) and IGFBP5 (P = 0.0002 and P = 0.006, respectively) were up-regulated in the tumours when compared with the adjacent normal myometrium. Conclusions: The integrative genomic and transcriptomic approach indicated that FGFR1 and IGFBP5 amplification, as well as the consequent up-regulation of the protein products, plays an important role in the aetiology of ULs and thus provides data for potential drug therapies development to target genes associated with cellular proliferation in ULs. © 2013 Cirilo et al.en
dc.description.affiliationDepartment of Genetics Institute of Biosciences UNESP - São Paulo State University, Botucatu, São Paulo
dc.description.affiliationCIPE - NeoGene Laboratory, AC Camargo Hospital Fundação Antonio Prudente, São Paulo, São Paulo
dc.description.affiliationInter-institutional Grad Program on Bioinformatics Institute of Mathematics and Statistics USP - São Paulo University, São Paulo, São Paulo
dc.description.affiliationDepartment of Anatomic Pathology AC Camargo Hospital Fundação Antonio Prudente, São Paulo, São Paulo
dc.description.affiliationDepartment of Pathology School of Medicine UNESP - São Paulo State University, Botucatu, São Paulo
dc.description.affiliationOntario Cancer Institute The Campbell Family Institute for Cancer Research, and Techna Institute University Health Network, Toronto, ON
dc.description.affiliationDepartment of Gynaecology and Obstetrics School of Medicine São Paulo State University, Botucatu, São Paulo
dc.description.affiliationDepartment of Urology School of Medicine UNESP - São Paulo State University, Botucatu, São Paulo
dc.description.affiliationUnespDepartment of Genetics Institute of Biosciences UNESP - São Paulo State University, Botucatu, São Paulo
dc.description.affiliationUnespDepartment of Pathology School of Medicine UNESP - São Paulo State University, Botucatu, São Paulo
dc.description.affiliationUnespDepartment of Gynaecology and Obstetrics School of Medicine São Paulo State University, Botucatu, São Paulo
dc.description.affiliationUnespDepartment of Urology School of Medicine UNESP - São Paulo State University, Botucatu, São Paulo
dc.identifierhttp://dx.doi.org/10.1371/journal.pone.0057901
dc.identifier.citationPLoS ONE, v. 8, n. 3, 2013.
dc.identifier.doi10.1371/journal.pone.0057901
dc.identifier.file2-s2.0-84874582462.pdf
dc.identifier.issn1932-6203
dc.identifier.lattes0514178654667684
dc.identifier.lattes2259986546265579
dc.identifier.lattes0585723113037140
dc.identifier.scopus2-s2.0-84874582462
dc.identifier.urihttp://hdl.handle.net/11449/74797
dc.identifier.wosWOS:000315634900051
dc.language.isoeng
dc.relation.ispartofPLOS ONE
dc.relation.ispartofjcr2.766
dc.relation.ispartofsjr1,164
dc.rights.accessRightsAcesso aberto
dc.sourceScopus
dc.subjectBRCA1 protein
dc.subjectFanconi anemia group A protein
dc.subjectfibroblast growth factor receptor 1
dc.subjectsomatomedin binding protein 5
dc.subjecttumor marker
dc.subjectadult
dc.subjectcell proliferation
dc.subjectcomparative genomic hybridization
dc.subjectcomputer model
dc.subjectdata analysis
dc.subjectfemale
dc.subjectgene expression
dc.subjectgene identification
dc.subjectgenetic algorithm
dc.subjectgenetic screening
dc.subjectgenomics
dc.subjecthuman
dc.subjecthuman cell
dc.subjecthuman tissue
dc.subjectmajor clinical study
dc.subjectmicroarray analysis
dc.subjectmolecular biology
dc.subjectmyometrium
dc.subjectnucleotide sequence
dc.subjectprotein analysis
dc.subjectprotein protein interaction
dc.subjecttarget cell
dc.subjecttissue section
dc.subjecttranscriptomics
dc.subjecttumor gene
dc.subjectupregulation
dc.subjectuterus myoma
dc.subjectCell Proliferation
dc.subjectCluster Analysis
dc.subjectDatabases, Genetic
dc.subjectDNA Copy Number Variations
dc.subjectFemale
dc.subjectGene Expression Profiling
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGenes, Neoplasm
dc.subjectGenomics
dc.subjectHepatic Stellate Cells
dc.subjectHumans
dc.subjectImmunohistochemistry
dc.subjectInsulin-Like Growth Factor Binding Protein 5
dc.subjectLeiomyoma
dc.subjectMicroRNAs
dc.subjectProtein Interaction Maps
dc.subjectReceptor, Fibroblast Growth Factor, Type 1
dc.subjectReproducibility of Results
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectSignal Transduction
dc.subjectUterine Neoplasms
dc.titleAn Integrative Genomic and Transcriptomic Analysis Reveals Potential Targets Associated with Cell Proliferation in Uterine Leiomyomasen
dc.typeArtigo
dcterms.licensehttp://www.plos.org/open-access/
unesp.author.lattes0514178654667684
unesp.author.lattes2259986546265579
unesp.author.lattes0585723113037140
unesp.author.orcid0000-0001-5815-8423[2]
unesp.author.orcid0000-0003-3893-5269[3]
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências, Botucatupt
unesp.campusUniversidade Estadual Paulista (Unesp), Faculdade de Medicina, Botucatupt

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