Epigenetic Silencing of theHIC-1Gene in Human Medulloblastomas

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Abstract
The HIC-1 (hypermethylated in cancer) candidate tumor suppressor gene is located on chromosome 17p13.3, a region frequently deleted in medulloblastomas (MBs). MBs arising in the cerebellum represent the most common malignant brain tumors in children. In this study we have analyzed the sequence, methylation, and expression status of the HIC-1 gene in MBs. Hypermethylation of the 5'UTR and/or second exon of HIC-1 was detected in 33/39 (85%) of MB biopsies and in 7/8 (88%) of MB cell lines by methylation-specific PCR. There was a significant correlation (p < 0.001) between HIC-1 methylation and lack of transcription as determined by competitive RT-PCR. Treatment of the MB cell lines Daoy and MEB-MED-8A with 5-aza-2'deoxycytidine led to re-expression of HIC-1 transcripts, indicating a silencing of HIC-1 by CpG island methylation. Mutation analysis of the coding region of HIC-1 revealed a single deletion leading to an in-frame deletion of 4 amino acids in the second exon of HIC-1 (1/68, 1.5%). Our data indicate that a significant number of MBs exhibit strikingly reduced HIC-1 expression caused by altered CpG island methylation. These data suggest that epigenetic silencing of HIC-1 may well contribute to the pathogenesis in the majority of MBs.