RESUMEN
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.
Asunto(s)
Neoplasias Encefálicas/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor/fisiología , Meduloblastoma/genética , Regiones Promotoras Genéticas/genética , Adolescente , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Cadherinas/genética , Caspasa 8 , Caspasas/genética , Niño , Preescolar , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Humanos , Lactante , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/secundario , O(6)-Metilguanina-ADN Metiltransferasa/genética , Inhibidor Tisular de Metaloproteinasa-3/genéticaRESUMEN
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.