RESUMO
AIMS AND BACKGROUND: The literature data show that the most frequently affected chromosomes in ovarian carcinogenesis are 1, 8 and 17. In the present study we aimed to define more precisely at a high resolution the genomic imbalances of these chromosomes in ovarian cancer and to determine genomic markers separating tumors of different histological types and stages. METHODS: Array comparative genomic hybridization (CGH) with a resolution of approximately 0.8 Mb was applied in 28 primary ovarian tumors. We identified regions of highly frequent gains or losses (affecting more than 40% of ovarian cancers) and determined sites showing alterations of elevated amplitude (amplifications or homozygous deletions). Doing this we also identified at least two adjacent changed clones. RESULTS: We determined anomalies strongly associated with the disease such as deletions at 8p21-23, 17p12-13, 1p35-36 or amplifications at 1q23, 17q12, 17q23.2, 8q13.2, 8q24. We defined more precisely the gains in 17q12-q24, finding as strong candidates for ovarian tumorigenesis the genes LASP1 (17q12), TGF11 (17q21.32), MUL (17q23.2), TBX2 (17q23.2), AXIN2 (17q24.3) and GRB2 (17q25.1). Of particular note was gain of 8q13.2, which occurred at a high frequency in ovarian cancer, especially in serous and late-stage tumors. We found that gains of 1q32-1q43, 8p11-p12, 8q11.23, 8q13.2, and 8q24.21-8q24.22 and losses of 1p36.21, 8p23.1-8p21.1 and 8q21.2 were associated with serous histology, whereas losses of 1q23 and 1q32-43 and gains of 17q11.2-12 and 17q25 were associated with mucinous histology. Gains of 1q23, 8q24, 17q23.2, 17q24.2 and losses of 1p35-36, 8p, 17p, and 17q were specific for late-stage ovarian cancers. CONCLUSIONS: Our study has identified potential genomic markers of interest on chromosomes 1, 8 and 17 in ovarian cancer. Tumors showed a wide variety in the patterns of alteration, suggesting that alternative mechanisms of genomic instability may play a role in this tumor type.
Assuntos
Cromossomos Humanos Par 17 , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 8 , Hibridização Genômica Comparativa , Marcadores Genéticos , Instabilidade Genômica , Neoplasias Ovarianas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma Mucinoso/genética , Adulto , Idoso , Proteína Axina , Cistadenocarcinoma Seroso/genética , Proteínas do Citoesqueleto/genética , Feminino , Proteína Adaptadora GRB2/genética , Humanos , Proteínas com Domínio LIM , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Neoplasias Ovarianas/patologia , Deleção de Sequência , Proteínas com Domínio T/genética , Fator de Crescimento Transformador alfa/genética , Proteínas com Motivo Tripartido , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND: We selected 5 oncogenes with well-established roles in carcinogenesis -- CCND1, ErbB1, ErbB2, c-myc and ZNF217 -- to investigate the coexistence of their copy imbalances in relation to the clinico-pathological characteristics of ovarian tumors. MATERIALS AND METHODS: Fluorescence in situ hybridization for the 5 genes was applied to a preexisting tissue microarray. 38 ovarian tumors were successfully analyzed for copy number changes of the 5 genes. RESULTS: At least one of these oncogenes was gained/amplified in 27 out of 38 tumors (71.1%). We report the highest frequency of c-myc genetic gain/amplification since it affected 42.1% of the ovarian tumors. We observed sequential involvement of copy number alterations of the other genes in the presence of c-myc disruption. The incidence of copy number changes of the 5 oncogenes -- both single and combinatorial -- was higher in high-grade tumors. All double aberrations in the serous group comprised c-myc and ZNF217copy number increases. CONCLUSIONS: Our results revealed a combination between copy number increases of c-myc and ZNF217, associated with serous histology. The data from this combined analysis of the 5 oncogenes could be used as a basis in considering the combined approach in molecular-based therapy of ovarian cancer.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Ciclina D1/genética , Dosagem de Genes/genética , Proteínas Oncogênicas v-erbB/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transativadores/genética , Bulgária/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , IncidênciaRESUMO
This study aimed to clarify the molecular mechanisms involved in ovarian carcinogenesis, and to identify candidate molecular targets for its diagnosis and treatment. The genome-wide gene expression profiles of 22 epithelial ovarian carcinomas were analyzed with a microarray representing 38,500 genes, in combination with laser microbeam microdissection. A total of 273 commonly up-regulated transcripts and 387 down-regulated transcripts were identified in the ovarian carcinoma samples. Of the 273 up-regulated transcripts, only 87 (31.9%) were previously reported as up-regulated in microarray studies using bulk cancer tissues and normal ovarian tissues for analysis. CHMP4C (chromatin-modifying protein 4C) was frequently overexpressed in ovarian carcinoma tissue, but not expressed in the normal human tissues used as a control. Our data should contribute to an improved understanding of tumorigenesis in ovarian cancer, and aid in the development of diagnostic tumor markers and molecular-targeting therapy for patients with the disease.
