Aberrant promoter methylation of previously unidentified target genes is acommon 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 medu lloblastomas and other primitive neuroectodermal tumors (PNETs) of the chil dhood CNS we performed a systematic analysis of gene specific and global me thylation. 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 a bnormalities by SSCP. Immunohistochemistry for p16 was negative in all exam ined normal cerebella and medulloblastomas. Using the technique of Restrict ion 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 p atterns differed between medulloblastomas and PNETs. Examination of several methylated sequences revealed homologies to known genes and expressed sequ ences. Analysis of survival data identified seven of 30 hypermethylated seq uences significantly correlating with poor prognosis. We suggest that DNA h ypermethylation has an outstanding potential for the identification of nove l tumor suppressors as well as diagnostic and therapeutic targets in MBs an d other PNETs of the CNS.