Promoter methylation pattern of caspase-8, P16INK4A, MGMT, TIMP-3, and E-cadherin in medulloblastoma.
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.
Ebinger
Martin
M
Department of Molecular Pathology, Institute of Pathology, Tübingen, Germany.
Senf
Leonore
L
Wachowski
Olga
O
Scheurlen
Wolfram
W
D000293:Adolescent; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D015820:Cadherins / Q000235:genetics; D053181:Caspase 8; D020169:Caspases / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics
D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019717:Tissue Inhibitor of Metalloproteinase-3; D019853:O(6)-Methylguanine-DNA Methyltransferase; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases