RESUMO
Methylation of promoter regions of CpG-rich sites is an important mechanism for silencing of tumor suppressor genes (TSG). To evaluate the role of tumor suppressor genes caspase-8 (CASP8), TIMP-3, E-cadherin (CDH1), p16INK4A, and MGMT in medulloblastoma tumorigenesis, 51 medulloblastomas (46 primary tumor specimens, 5 cell lines) were screened for methylation of promoter linked CpG-islands. For CASP8, we examined the 5' UTR region that has been shown to be associated with expression of CASP8. As detected by methylation specific PCR, methylation rate was low for TIMP-3 (3% of tumor samples; 1/5 cell lines), for MGMT (0% of tumor samples; 1/5 cell lines), for p16INK4A (2% of tumor samples; 2/5 cell lines) and for CDH1 (8% of tumor samples; 1/4 cell lines). CASP8, however, was methylated in 90% of tumor samples and 4/5 cell lines examined. Screening other tumor entities for CASP8 methylation, we found a similarly high level in 6 neuroblastoma cell lines in contrast to 5 osteosarcoma-, 4 Ewing's sarcoma- and 6 non-embryonic tumor cell lines without any increased promoter methylation. From our results we conclude that methylation of the CASP8 5' UTR region may play a role in inactivation of CASP8 in neural crest tumors.
Assuntos
Neoplasias Encefálicas/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Meduloblastoma/genética , Regiões Promotoras Genéticas/genética , Adolescente , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Caderinas/genética , Caspase 8 , Caspases/genética , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Humanos , Lactente , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/secundário , O(6)-Metilguanina-DNA Metiltransferase/genética , Inibidor Tecidual de Metaloproteinase-3/genéticaRESUMO
PURPOSE: We analyzed the prevalence, clinical pattern, and prognostic impact of CNS involvement in a large cohort of children and adolescents diagnosed with non-Hodgkin's lymphoma (NHL), with special attention to differences according to NHL subtype. PATIENTS AND METHODS: From October 1986 to December 2002, 2,381 patients (median age, 9.37 years; range, 0.2 to 23.8 years; female-to-male ratio, 1:2.7) from Germany, Austria, and Switzerland were registered. A total of 2,086 patients were eligible for the consecutive multicenter protocols NHL-Berlin-Frankfurt-Münster [BFM] -86, NHL-BFM-90, and NHL-BFM-95, and could be evaluated for outcome. RESULTS: CNS involvement was diagnosed in 141 (5.9%) of 2,381 patients and was associated with an advanced stage of NHL. The percentage of CNS-positive patients was 8.8% for Burkitt's lymphoma/Burkitt's leukemia (BL/B-ALL), 5.4% for precursor B-lymphoblastic lymphoma (pB-LBL), 3.3% for anaplastic large-cell lymphoma, 3.2% for T-cell-LBL, 2.6% for diffuse large B-cell lymphoma, and 0% for primary mediastinal large B-cell NHL (P < .001). Most CNS-positive patients with pB-LBL, T-LBL, or BL/B-ALL had meningeal disease. The probability of event-free survival (pEFS; +/- SE) at 5 years was 85% +/- 1% for the 2,086 protocol patients (median follow-up, 6.5 years; range, 0.3 to 17.7 years). For the 112 CNS-positive patients, pEFS was 64% +/- 5%, compared with 86% +/- 1% for the 1,927 CNS-negative patients (P < .001). Although CNS disease had no impact on pEFS for advanced-stage T-LBL patients, CNS-positive patients with BL/B-ALL had a worse average outcome than CNS-negative patients with stage IV BL/B-ALL (60% +/- 5% v 81% +/- 3%; P < .001). In multivariate analysis, CNS disease was the strongest predictor for relapse in BL/B-ALL patients with advanced-stage disease. CONCLUSION: Six percent of childhood/adolescent NHL patients were CNS positive. However, the prevalence, pattern, and prognostic impact of CNS involvement differed among NHL subtypes.
Assuntos
Neoplasias Encefálicas/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Linfoma não Hodgkin/classificação , Linfoma não Hodgkin/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Neoplasias Epidurais/epidemiologia , Neoplasias Epidurais/terapia , Feminino , Alemanha/epidemiologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Lactente , Recém-Nascido , Linfoma não Hodgkin/terapia , Masculino , Análise Multivariada , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prevalência , Prognóstico , Falha de Tratamento , Resultado do TratamentoRESUMO
Expression of growth arrest-specific (Gas) genes is observed during growth arrest in terminally differentiating cells during development of peripheral nerves. Gas7 is expressed predominantly in the brain and is required for neurite formation. Human GAS7 is located on chromosome 17p11.3 close to or within the putative breakpoint of isochromosome 17q (i(17q)) in medulloblastoma, indicating a potential role as a tumor suppressor gene, lost by formation of i(17q). However in the present study, the expression of GAS7 was detected in 20 of 29 childhood medulloblastoma samples regardless of the presence of i(17q). Therefore, GAS7 is not likely to be a tumor suppressor gene in medulloblastoma development.