Loss of Heterozygosity on Chromosome 10, 13, 17 and p53 Gene Mutations in Human Brain Gliomas

Lee, Seung Hoon; Kim, Jong Hyun; Rhee, Chang Hun; Kang, Young Soon; Lee, Je Ho; Choi, Kil Soo

Abstract

Gliomas, the most common primary tumors of the human central nervous system, are usually malignant and virtually incurable. They can be classified according to their cellular differentiation:astrocytoma, oligodendroglioma, and ependymoma. The majority of these brain tumors are astrocytomas, which typically progress through three histopathologically defined stages with the passage of time:one premalignant stage, low-grade astrocytoma, and two malignant stages, anaplastic astrocytoma and glioblastoma multiforme. Recent studies on the molecular mechanisms of carcinogensis have demonstrated a possible role for two classes of genes in neoplastic transformation:tumor suppressor genes and oncogenes. Tumor suppressor genes are wild-type alleles of genes that are believed to function normally in the cell to suppress cellular proliferation. Inactivation of both copies of suppressor gene may contribute to neoplastic transformation by removing a normal constraint to cell growth. The well characterised suppressor genes are RB gene and p53 gene. Gliomas, like most other cancers, are associated with several genetic changes, including oncogenes and suppressor genes. In an attempt to further our knowledge of tumor suppressor genes contributing glioma development and progression, restriction fragment length polymorphism(RFLP) analysis was done to determine loss of heterozygosity(LOH) on chromosome 10. 13q(RBI), 17p, and 22q containing putative tumor suppressor genes in 36 cases of human gliomas with various malignancy grades. And to detect p53 gene mutations at exon 5, 6, and 7 in 23 cases of malignant gliomas, polymerase chain reaction-single strand conformation polymorphisms(PCR-SSCP) analysis was performed. Loss of heterozygosity for loci on chromosome 10 were found in four of 5(60%) informative cases of glioblastoma multiforme and one of 2(50%) cases of anaplastic astrocytomas. Loss of heterozygosity on chromosome 17p was found in eight of 17(47%) informative cases of malignant gliomas, including 2 cases of anaplastic oligodendroglioma. There was no allelic loss of chromosome 10 and 17 in benign gliomas. Deletions on RBI locus were seen in six of 10(60%) informative cases of glioblastoma multiforme and two of 5(40%) informative cases of low-grade astrocytomas, suggesting that RBI gene may have a role associated with the early events in tumorigenesis. In PCR-SSCP analysis, six of 23(26%) cases of malignant gliomas, including one case of anaplastic oligodendroglioma, showed mobility shifts on exon 5 or 7 of p53 gene which suggest point mutations of this gene. There was no LOH at IGLC2 locus on chromosome 22. On the basis of the data presented here, it is possible to associate certain molecular abnormalities with gliomas of increasing grades of malignancy, deletion of RB gene, loss of heterozygosity on chromosome 17p, p53 gene mutation, and loss of allele on chromosome 10.