Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma

Medulloblastoma is the most common malignant brain tumor in children. Chromosome arm 17p13.3 is reduced to homozygosity in 35-50% of medulloblastomas,making it the most frequent genetic alteration in these tumors. HIC-1 (hypermethylated in cancer) is a putative tumor suppressor gene located in the a...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2002-07, Vol.62 (13), p.3794-3797
Main Authors: ROOD, Brian R, HUIZHEN ZHANG, WEITMAN, David M, COGEN, Philip H
Format: Article
Language:English
Subjects:
Biological and medical sciences
Brain Neoplasms - genetics
Brain Neoplasms - therapy
Chromosomes, Human, Pair 17
CpG Islands - genetics
DNA Methylation
Humans
Kruppel-Like Transcription Factors
Loss of Heterozygosity
Medical sciences
Medulloblastoma - genetics
Medulloblastoma - therapy
Neurology
Transcription Factors - genetics
Treatment Outcome
Tumors of the nervous system. Phacomatoses
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Summary:Medulloblastoma is the most common malignant brain tumor in children. Chromosome arm 17p13.3 is reduced to homozygosity in 35-50% of medulloblastomas,making it the most frequent genetic alteration in these tumors. HIC-1 (hypermethylated in cancer) is a putative tumor suppressor gene located in the area of common deletion. HIC-1 resides in a CpG island and is hypermethylated in many different tumor types. Therefore, we studied a series of tumor specimens for hypermethylation and deletion of the region containing the HIC-1 gene to determine whether these two mechanisms of gene inactivation play a complimentary role in medulloblastoma. Southern blotting was performed using the methylation-sensitive restriction endonuclease NotI. Methylation of NotI restriction sites located in HIC-1 was demonstrated in 26 (72%) of 36 tumors and 11 (92%) of 12 specimens of normal brain. Of these 26 tumors, 23 differed significantly from normal brain. A greater proportion of the cells from the tumors showed methylated alleles of the HIC-1 gene. A group of 15 (42%) of 36 tumors exhibited loss of heterozygosity (LOH) for DNA sequences located on chromosome arm 17p. There was no significant correlation between LOH and methylation status (P = 0.19). Methylation in tumors beyond that seen in normal brain predicted poor overall survival independent of clinical risk category (P = 0.014). The results of our study show that methylation of the CpG island that contains the HIC-1 gene is common in medulloblastoma and, together with LOH of 17p, may be a critical event in the formation and aggressiveness of this tumor.
ISSN:0008-5472
1538-7445