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[Cancer Research 62, 3794-3797, July 1, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

Hypermethylation of HIC-1 and 17p Allelic Loss in Medulloblastoma1

Brian R. Rood2,,3, Huizhen Zhang, David M. Weitman and Philip H. Cogen

Departments of Pediatric Hematology/Oncology [B. R. R.] and Pediatric Neurosurgery [H. Z., D. M. W., P. H. C.], Children’s Research Institute, Children’s National Medical Center, Washington, D.C. 20010

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.




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