Alterações genômicas e perfil de expressão gênica global em leiomiomas uterinos
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Data
2011-06-22
Autores
Cirilo, Priscila Daniele Ramos [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Os Leiomiomas Uterinos (LU) são os tumores benignos mais comuns do trato genital feminino afetando entre 25-30% das mulheres em idade reprodutiva. Embora com etiologia pouca conhecida, estes tumores constituem um importante problema de saúde pública, sendo a principal indicação para histerectomia. Aproximadamente 40- 50% dos LU apresentam anormalidades citogenéticas não randômicas, portanto, a outra metade pode conter alterações submicroscópicas, como as alterações no número de cópias de DNA (CNVs). Estudos de expressão gênica globais têm revelado o envolvimento de genes que participam das vias de proliferação e ciclo celular, do ácido retinóico, sinalização TGF-beta e IGF-1 em resposta ao estrógeno e a progesterona. Entretanto, poucos genes mapeados em regiões de CNVs foram diretamente associados com o desenvolvimento dos LU. O objetivo deste estudo foi investigar alterações no número de cópias de DNA em pacientes com LU múltiplos e únicos. Utilizando a técnica de CGH array, foram avaliadas 80 amostras de LU obtidas de 56 pacientes. O perfil de expressão gênica global foi investigado em 51 amostras com o objetivo de identificar genes diferencialmente expressos em relação ao miométrio adjacente (MM). Posteriormente, os dados genômicos e transcriptômicos foram integrados com o objetivo de identificar CNVs funcionais que possam estar associadas ao fenótipo tumoral, sendo esta análise importante para a descrição de novos marcadores moleculares e possíveis alvos terapêuticos. Amostras de DNA e RNA foram obtidas dos LU e MM de pacientes nas fases proliferativa e secretora do ciclo menstrual. As 80 amostras de DNA tumoral e DNA referência universal foram digeridas, marcadas e hibridadas em lâminas Agilent Human 4x44K CGH Microarrays. Os dados foram...
Uterine leiomyomas (UL) are the most common benign tumors affecting between 25- 30% of women in reproductive age. Although little is known about its etiology, these tumors represent a major problem in public health being the main indication for hysterectomy. About 40-50% have nonrandom cytogenetic abnormalities, thus half of these tumors may have submicroscopic alterations, as well as copy number variations (CNVs). Global gene expression studies have shown genes that act in proliferation and cell cycle process, retinoic acid, TGF-beta and IGF-1 signaling in response to estrogen and progesterone. However, few genes mapped at CNVs regions were directly associated with the UL development. The aim of this study was to investigate DNA copy number alterations in patients with multiple and unique UL. For this, the CGH array technique was employed in 80 samples obtained from 56 patients. The global gene expression profile was investigated in 51 samples to identify differentially expressed genes in relation to adjacent myometrium (MM). In order to identify functional CNVs that might be associated with tumor phenotype, the genomic and transcriptomic data were evaluated using integrative analysis, which is crucial to describe new molecular markers and putative therapeutic targets. DNA and RNA samples were obtained from UL and MM of patients in the proliferative and secretory menstrual cycle phases. Eighty DNA samples and reference DNA were digested, labeled and hybridized in Agilent Human CGH Microarrays 4x44K slides. Data were analyzed by Nexus v5.0 with the Rank Segmentation algorithm and 1.00 E-4 threshold. The classification of nonrandom CNVs (P ≤ 0.05) was the presence in more than 10% cases and exclusion of CNVs detected in more than 5% of the population... (Complete abstract click electronic access below)
Uterine leiomyomas (UL) are the most common benign tumors affecting between 25- 30% of women in reproductive age. Although little is known about its etiology, these tumors represent a major problem in public health being the main indication for hysterectomy. About 40-50% have nonrandom cytogenetic abnormalities, thus half of these tumors may have submicroscopic alterations, as well as copy number variations (CNVs). Global gene expression studies have shown genes that act in proliferation and cell cycle process, retinoic acid, TGF-beta and IGF-1 signaling in response to estrogen and progesterone. However, few genes mapped at CNVs regions were directly associated with the UL development. The aim of this study was to investigate DNA copy number alterations in patients with multiple and unique UL. For this, the CGH array technique was employed in 80 samples obtained from 56 patients. The global gene expression profile was investigated in 51 samples to identify differentially expressed genes in relation to adjacent myometrium (MM). In order to identify functional CNVs that might be associated with tumor phenotype, the genomic and transcriptomic data were evaluated using integrative analysis, which is crucial to describe new molecular markers and putative therapeutic targets. DNA and RNA samples were obtained from UL and MM of patients in the proliferative and secretory menstrual cycle phases. Eighty DNA samples and reference DNA were digested, labeled and hybridized in Agilent Human CGH Microarrays 4x44K slides. Data were analyzed by Nexus v5.0 with the Rank Segmentation algorithm and 1.00 E-4 threshold. The classification of nonrandom CNVs (P ≤ 0.05) was the presence in more than 10% cases and exclusion of CNVs detected in more than 5% of the population... (Complete abstract click electronic access below)
Descrição
Palavras-chave
Genética, Leiomioma uterino
Como citar
CIRILO, Priscila Daniele Ramos. Alterações genômicas e perfil de expressão gênica global em leiomiomas uterinos. 2011. 232 f. Tese (doutorado) - Universidade Estadual Paulista, Instituto de Biociências de Botucatu, 2011.