RESUMO
The increased chemosensitivity of oligodendroglial tumours has been associated with loss of heterozygosity (LOH) of the p arm of chromosome 1 and the q arm of chromosome 19 (LOH 1p/19q). Other clinical and molecular factors have also been identified as being prognostic and predictive of treatment outcome. We reviewed 105 patients with oligodendroglioma treated at a single centre over 20 years. Median survival in oligodendroglioma patients with LOH 1p/19q was significantly longer (10.9 vs. 2.0 years). In the anaplastic oligodendroglioma group, univariate analysis demonstrated decreased patient age, presentation with seizures, use of adjuvant chemotherapy and LOH 1p/19q as predictors of improved survival. Multivariate analysis confirmed LOH 1p/19q as a significant predictor of improved survival (hazard ratio, 3.4; p=0.015). Median survival in patients with anaplastic oligodendroglioma with LOH 1p/19q was 15.4 years vs. 1.2 years for those without LOH 1p/19q. This study confirms the utility of LOH 1p/19q as a prognostic marker in oligodendroglioma.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Oligodendroglioma/genética , Oligodendroglioma/mortalidade , Adulto , Idoso , Neoplasias Encefálicas/patologia , Quimioterapia Adjuvante , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/patologia , Prognóstico , Modelos de Riscos Proporcionais , Proteína Supressora de Tumor p53/metabolismo , Adulto JovemRESUMO
The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Genes Supressores de Tumor , Glioblastoma/genética , Proteínas Associadas aos Microtúbulos/genética , Oncogenes , Proteínas Supressoras de Tumor/genética , Variações do Número de Cópias de DNA , Expressão Gênica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Humanos , Mutação , Reação em Cadeia da Polimerase , Transdução de SinaisRESUMO
Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.
Assuntos
Neoplasias Encefálicas/genética , Regulação da Expressão Gênica/genética , Glioblastoma/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Carmustina/farmacologia , Proteínas de Ciclo Celular , Criança , Resistencia a Medicamentos Antineoplásicos/genética , Amplificação de Genes , Expressão Gênica , Estudo de Associação Genômica Ampla , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Immunoblotting , Hibridização in Situ Fluorescente , Camundongos , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Reduction in the mRNA and protein expression of lipocalin-like prostaglandin D(2) (PGD(2)) synthase (PGDS), the main arachidonic acid metabolite produced in neurons and glial cells of the central nervous system, is a significant biological event involved in the malignant progression of astrocytomas and is predictive of poor survival. In vitro, the addition of the main PGDS metabolite, PGD(2), to A172 glioblastoma cells devoid of PGDS resulted in antiproliferative activity and cell death. In vitro PGD(2) substitution also enhanced the efficacy of cyclo-oxygenase-2 inhibitors. This finding has exciting implications for early interventional efforts for the grade 2 and 3 astrocytomas.
Assuntos
Astrocitoma/enzimologia , Astrocitoma/patologia , Oxirredutases Intramoleculares/deficiência , Astrocitoma/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Metilação de DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Oxirredutases Intramoleculares/genética , Íntrons/genética , Lipocalinas/genética , Análise Multivariada , Modelos de Riscos Proporcionais , Prostaglandina D2/farmacologia , Transporte Proteico/efeitos dos fármacos , Análise de SobrevidaRESUMO
Clinical treatment decisions and the survival outcomes of patients with gliomas are directly impacted by accurate tumor classification. New and more reliable prognostic markers are needed to better identify the variable duration of survival among histologically defined glioma grades. Microarray expression analysis and immunohistochemistry were used to identify biomarkers associated with gliomas with more aggressive biologic behaviors. The protein expression of IQGAP1 and IGFBP2, when used in conjunction with the World Health Organization grading system, readily identified and defined a subgroup of patients with grade III gliomas whose prognosis was poor. In addition, in patients with glioblastoma multiforme, in whom IQGAP1 and IGFBP2 were absent, long-term survival of more than 3 years was observed. The use of these markers confirmed a nonuniform distribution of survival in those with World Health Organization grade III and IV tumors. Thus, IQGAP1 and IGFBP2 immunostaining supplements current histologic grading by offering additional prognostic and predictive information.