Genetic basis of glioma progression

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The most frequent and malignant brain tumor is the glioblastoma, which may develop de novo (primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). These glioblastoma subtypes constitute distinct disease entities that affect patients at different age, and evolve through different genetic pathways. Primary glioblastomas develop in older patients (mean age, 55 years) and typically show EGFR amplification/overexpression, LOH on the entire chromosome 10, PTEN mutations and, occasionally, MDM2 amplification. Secondary glioblastomas develop in younger patients (mean age, 40 years) and typically contain TP53 mutations and/or p14ARF promoter methylation as earliest detectable alterations. Additional changes in the pathway leading to secondary glioblastomas include LOH on 19q and 10q, and RB1 promoter methylation. Common to both primary and secondary glioblastoma is LOH on 10q, distal to the PTEN locus; a putative suppressor gene at 10q25-qter may be largely responsible for the glioblastoma phenotype.The etiology of human gliomas is largely unknown. Hereditary diseases predisposing to the development of gliomas e.g. Li-Fraumeni syndrome, Turcot syndrome, NF1, and NF2 syndromes are rare and cannot explain the development of most of human gliomas. The presence of SV40 large T sequence has been observed in a variety of human brain tumors including gliomas, and they are likely be originated from the contamination of SV40 in poliovaccine between 1955-1962. However, there is no direct evidence that SV40 infection is associated with pathogenesis of human brain tumors. There is recent evidence that G:C→A:T transition mutations at CpG sites in the TP53 gene are significantly more frequent in astrocytic tumors with promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) than in those without methylation. This may suggest that endogenous alkylating agents that produce O6-methylguanine or related adducts recognized by MGMT may be involved in the development of astrocytic brain tumors.(Communicated by Takashi SUGIMURA, M. J. A., March 12, 2003)
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Genetic basis of glioma progression

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