RESUMO
Alterations of DNA copy number are believed to be important indicators of tumor progression in human astrocytoma. We used an array of bacterial artificial chromosomes to map relative DNA copy number in 50 primary glioblastoma multiforme tumors at approximately 1.4-Mb resolution. We identified 33 candidate sites for amplification and homozygous deletion in these tumors. We identified three major genetic subgroups within these glioblastoma multiforme tumors: tumors with chromosome 7 gain and chromosome 10 loss, tumors with only chromosome 10 loss in the absence of chromosome 7 gain, and tumors without copy number change in chromosomes 7 or 10. The significance of these genetic groups to therapeutics needs further study.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Hibridização de Ácido Nucleico/métodos , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Aberrações Cromossômicas , Análise por Conglomerados , Glioblastoma/genética , Humanos , Hibridização in Situ Fluorescente , Reprodutibilidade dos Testes , Análise de SobrevidaRESUMO
BACKGROUND: Medulloblastomas are the most common primary malignant childhood intracranial neoplasms. Patients are currently sorted into three risk groups based on clinical criteria: standard, poor, and infant (<18 months old). We hypothesized that genetic copy number aberrations (CNA) predict prognosis and would provide improved criteria for predicting outcome. METHODS: DNA from 35 medulloblastoma patients from four Children's Cancer Group trials was analyzed by comparative genomic hybridization to determine CNAs. The genetic alterations were evaluated using statistical and cluster analyses. RESULTS: The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p, 10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected. Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P = 0.03) and event-free survival (P = 0.04) independent of poor risk group classification. Age <3 tended to be associated with <3 CNAs (P = 0.06). Unsupervised cluster analysis sorted the study patients into four subgroups based on CNAs. Supervised analysis using the program Significance Analysis of Microarrays (SAM) quantitatively validated those CNAs identified by unsupervised clustering that significantly distinguished among the four subgroups. CONCLUSIONS: Medulloblastomas are genetically heterogeneous and can be categorized into separate genetic subgroups by their CNAs using unsupervised cluster analysis and SAM. i(17)(q10) was a significant independent negative prognostic factor. Infant medulloblastomas may be a distinct genetic subset from those of older patients.
Assuntos
Neoplasias Cerebelares/patologia , Cromossomos Humanos Par 17/genética , Isocromossomos , Meduloblastoma/patologia , Adolescente , Neoplasias Cerebelares/genética , Criança , Pré-Escolar , Aberrações Cromossômicas/classificação , Análise por Conglomerados , Feminino , Genoma Humano , Humanos , Lactente , Masculino , Meduloblastoma/genética , Hibridização de Ácido Nucleico/métodos , Prognóstico , Fatores de Risco , Análise de SobrevidaRESUMO
Chromosome 7 is a frequent site of cytogenetic aberrations in human astrocytomas. One region that is often targeted in human astrocytomas is on 7p. The U251 human glioblastoma cell line has a region of gain of genetic material on 7p similar to that seen in human astrocytomas. We used several cytogenetic techniques to study chromosome 7 in U251 cells and identified a complex rearrangement that accounts for gain of chromosome 7 genetic material in the cell line. The characteristic rearrangement suggests a mechanism leading to 7p gain in primary grade IV astrocytomas.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 7 , Humanos , Hibridização in Situ Fluorescente , CariotipagemRESUMO
Glioblastoma multiforme (GM) is the most lethal form of brain tumor, with a median survival of approximately 1 year. Treatment options are limited. Radiation therapy is a common form of treatment, but many tumors are resistant. In earlier studies, we found that gain of chromosome 7 is associated with radiation resistance in human primary GM. In this study, we extend that result to a model system in which we transferred chromosome 7 to recipient cells and confirmed radiation resistance as a function of chromosome 7 gain. We identified three candidate regions on chromosome 7 that conferred radiation resistance in our model system.