Da Cirilo, Priscilaniele Ramos [UNESP]Marchi, Fábio Albuquerquede Barros Filho, Mateus CamargoRocha, Rafael MalagoliDomingues, Maria Aparecida Custódio [UNESP]Jurisica, IgorPontes, Anaglória [UNESP]Rogatto, Silvia Regina [UNESP]2014-05-272014-05-272013-03-04PLoS ONE, v. 8, n. 3, 2013.1932-6203http://hdl.handle.net/11449/74797Background: 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.engBRCA1 proteinFanconi anemia group A proteinfibroblast growth factor receptor 1somatomedin binding protein 5tumor markeradultcell proliferationcomparative genomic hybridizationcomputer modeldata analysisfemalegene expressiongene identificationgenetic algorithmgenetic screeninggenomicshumanhuman cellhuman tissuemajor clinical studymicroarray analysismolecular biologymyometriumnucleotide sequenceprotein analysisprotein protein interactiontarget celltissue sectiontranscriptomicstumor geneupregulationuterus myomaCell ProliferationCluster AnalysisDatabases, GeneticDNA Copy Number VariationsFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticGenes, NeoplasmGenomicsHepatic Stellate CellsHumansImmunohistochemistryInsulin-Like Growth Factor Binding Protein 5LeiomyomaMicroRNAsProtein Interaction MapsReceptor, Fibroblast Growth Factor, Type 1Reproducibility of ResultsReverse Transcriptase Polymerase Chain ReactionSignal TransductionUterine NeoplasmsArtigo10.1371/journal.pone.0057901WOS:000315634900051Acesso aberto2-s2.0-848745824622-s2.0-84874582462.pdf051417865466768422599865462655790585723113037140