Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas--implications for tumor biology and potential clinical utility.
Medulloblastomas exhibit an array of diverse cytogenetic abnormalities. To evaluate the significance of epigenetic rather than genetic lesions in medulloblastomas and other primitive neuroectodermal tumors (PNETs) of the childhood CNS we performed a systematic analysis of gene specific and global methylation. Methylation-specific PCR detected no methylation for p15(INK4B), von Hippel Lindau and TP53 and only limited methylation for E-Cadherin and p16(INK4A) in tumors. The cell lines Daoy and MHH-PNET-5 in which the p16(INK4A) promoter was methylated did not express the gene, but demonstrated abnormalities by SSCP. Immunohistochemistry for p16 was negative in all examined normal cerebella and medulloblastomas. Using the technique of Restriction Landmark Genomic Scanning we detected methylation affecting up to 1% of all CpG islands in primary MB/PNETs and 6% in MB cell lines. Methylation patterns differed between medulloblastomas and PNETs. Examination of several methylated sequences revealed homologies to known genes and expressed sequences. Analysis of survival data identified seven of 30 hypermethylated sequences significantly correlating with poor prognosis. We suggest that DNA hypermethylation has an outstanding potential for the identification of novel tumor suppressors as well as diagnostic and therapeutic targets in MBs and other PNETs of the CNS.
Frühwald
M C
MC
Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Columbus, OH 43210, USA. fruhwald@uni-muenster.de
O'Dorisio
M S
MS
Dai
Z
Z
Tanner
S M
SM
Balster
D A
DA
Gao
X
X
Wright
F A
FA
Plass
C
C
D000293:Adolescent; D000328:Adult; D015820:Cadherins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000401:mortality*; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000401:mortality*; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D015820:Cadherins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins