Genetic pathways to glioblastomas.
Glioblastomas, the most frequent and malignant human brain tumors, may develop de novo (primary glioblastoma) or by progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). These glioblastoma subtypes constitute distinct disease entities that affect patients of different ages and develop through different genetic pathways. Our recent population-based study in the Canton of Zürich, Switzerland, shows that primary glioblastomas develop in older patients (mean age, 62 years) and typically show LOH on chromosome 10q (69%) and other genetic alterations (EGFR amplification, TP53 mutations, p16INK4a deletion, and PTEN mutations) at frequencies of 24-34%. Secondary glioblastomas develop in younger patients (mean, 45 years) and frequently show TP53 mutations (65%) and LOH 10q (63%). 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 responsible for the glioblastoma phenotype. Of the TP53 point mutations in secondary glioblastomas, 57% were located in hotspot codons 248 and 273, while in primary glioblastomas, mutations were more widely distributed. Furthermore, G:C-->A:T mutations at CpG sites were more frequent in secondary than in primary glioblastomas (56% vs 30%). These data suggest that the TP53 mutations in these glioblastoma subtypes arise through different mechanisms. There is evidence that G:C-->A:T transition mutations at CpG sites in the TP53 gene are significantly more frequent in low-grade astrocytomas with promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene than in those without methylation. This suggests that, in addition to deamination of 5-methylcytosine (the best known mechanism of formation of G:C-->A:T transitions at CpG sites), involvement of alkylating agents that produce O6-methylguanine or related adducts recognized by MGMT cannot be excluded in the pathway leading to secondary glioblastomas.
Ohgaki
Hiroko
H
International Agency for Research on Cancer, Lyon, France. ohgaki@iarc.fr
D000367:Age Factors; D001932:Brain Neoplasms / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D008875:Middle Aged