Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas–Implications for tumor biology and potential clinical utility

Abstract

Medulloblastomas exhibit an array of diverse cytogenetic abnormalities. To evaluate the signi®cance 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 speci®c and global methylation. Methylationspeci®c PCR detected no methylation for p15 INK4B, von Hippel Lindau and TP53 and only limited methylation for E-Cadherin and p16INK4A 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 aecting up to 1% of all CpG islands in primary MB/PNETs and 6% in MB cell lines. Methylation patterns diered between medulloblastomas and PNETs. Examination of several methylated sequences revealed homologies to known genes and expressed sequences. Analysis of survival data identi®ed seven of 30 hypermethylated sequences signi®cantly correlating with poor prognosis. We suggest that DNA hypermethylation has an outstanding potential for the identi®cation of novel tumor suppressors as well as diagnostic and therapeutic targets in MBs and other PNETs of the CNS. Oncogene (2001) 20, 5033 ± 5042.

SGNE1/7B2 is epigenetically altered and transcriptionally downregulated in human medulloblastomas

“…Recent studies have shown that the tumor suppressor genes RASSF1, Caspase 8 and HIC-1 are transcriptionally silenced by epigenetic alterations in medulloblastomas (Fru¨hwald et al, 2001;Waha et al, 2003;Lindsey et al, 2005). Methylation of the INK4C (CDKN2C) promoter and loss of p18 (INK4c) protein was detected in a significant fraction of medulloblastomas (Uziel et al, 2006).…”

DNA hypomethylation is prevalent even in low-grade breast cancers

“…1,3,4 Hypermethylation of certain CpG islands overlapping promoters can increase with tumor progression, although some of this regional hypermethylation begins very early in tumorigenesis. [5][6][7] Similarly, hypomethylation of tandem DNA repeats (satellite DNA or complex-sequence repeats) was associated with tumor progression in ovarian epithelial carcinomas and hepatocellular carcinomas and was a better predictor of poor survival than conventional markers. 8,9 By Southern blot analysis with a CpG methylation-sensitive restriction endonuclease, we have shown that satellite 2 DNA (Sat2), the main sequence in the long juxtacentromeric (centromere-adjacent) heterochromatin of chromosome 1 (Chr1), is often hypomethylated in breast adenocarcinomas and Wilms tumors as well as in ovarian epithelial carcinomas.…”

DNA methylation, imprinting and cancer

“…Fru Èhwald et al identified eight sequences in an RLGS scan that showed statistical significant correlation with survival of medulloblastoma patients. 85 Surprisingly, one of these methylation events correlated with improved outcome. RLGS analysis in AML patients identified a sequence within the WIT1 gene that was methylated at a higher frequency in relapsed AML as compared to diagnostic samples thus correlating with a chemoresistant phenotype.…”