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 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.
Rood
Brian R
BR
Department of Pediatric Hematology/Oncology, Children's Research Institute, Children's National Medical Center, Washington, DC. 20010, USA.
Zhang
Huizhen
H
Weitman
David M
DM
Cogen
Philip H
PH
D001932:Brain Neoplasms / Q000235:genetics* / Q000628:therapy; D002886:Chromosomes, Human, Pair 17; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D019656:Loss of Heterozygosity; D008527:Medulloblastoma / Q000235:genetics* / Q000628:therapy; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome
C096870:Hic1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors