An Integrative Genomic and Transcriptomic Analysis Reveals Potential Targets Associated with Cell Proliferation in Uterine Leiomyomas
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2013-03-04
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Background: 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.
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BRCA1 protein, Fanconi anemia group A protein, fibroblast growth factor receptor 1, somatomedin binding protein 5, tumor marker, adult, cell proliferation, comparative genomic hybridization, computer model, data analysis, female, gene expression, gene identification, genetic algorithm, genetic screening, genomics, human, human cell, human tissue, major clinical study, microarray analysis, molecular biology, myometrium, nucleotide sequence, protein analysis, protein protein interaction, target cell, tissue section, transcriptomics, tumor gene, upregulation, uterus myoma, Cell Proliferation, Cluster Analysis, Databases, Genetic, DNA Copy Number Variations, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Genomics, Hepatic Stellate Cells, Humans, Immunohistochemistry, Insulin-Like Growth Factor Binding Protein 5, Leiomyoma, MicroRNAs, Protein Interaction Maps, Receptor, Fibroblast Growth Factor, Type 1, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Uterine Neoplasms
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PLoS ONE, v. 8, n. 3, 2013.