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

Autor(es)

Ramos Cirilo, Priscila Daniele ^{[1, 2]} ; Marchi, Fabio Albuquerque ^{[1, 3]} ; Barros Filho, Mateus de Camargo ^[1] ; Rocha, Rafael Malagoli ^[4] ; Custodio Domingues, Maria Aparecida ^[5] ; Jurisica, Igor ^{[6, 7]} ; Pontes, Anagloria ^[8] ; Rogatto, Silvia Regina ^{[1, 9]}

Afiliação do(s) autor(es)

^[1] Fundacao Antonio Prudente, CIPE NeoGene Lab, AC Camargo Hosp, Sao Paulo - Brazil

^[2] UNESP Sao Paulo State Univ, Dept Genet, Inst Biosci, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Interinst Grad Program Bioinformat, Inst Math & Stat, Sao Paulo - Brazil

^[4] Fundacao Antonio Prudente, Dept Anat Pathol, AC Camargo Hosp, Sao Paulo - Brazil

^[5] UNESP Sao Paulo State Univ, Dept Pathol, Sch Med, Sao Paulo - Brazil

^[6] Campbell Family Inst Canc Res, Ontario Canc Inst, Toronto, ON - Canada

^[7] Univ Hlth Network, Techna Inst, Toronto, ON - Canada

^[8] Sao Paulo State Univ, Dept Obstet & Gynaecol, Sch Med, Sao Paulo - Brazil

^[9] UNESP Sao Paulo State Univ, Dept Urol, Sch Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 8, n. 3 MAR 4 2013.
• Citações Web of Science: 16

Resumo

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. (AU)

• Processo FAPESP: 07/51643-8 - Alteracoes no numero de copias de dna por cgh-array em leiomiomas uterinos.
• Beneficiário: Priscila Daniele Ramos Cirilo
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 08/58835-2 - Variacoes no numero de copias genomicas em leiomiomas uterinos de mulheres brasileiras
• Beneficiário: Silvia Regina Rogatto
• Modalidade de apoio: Auxílio à Pesquisa - Regular