Genetic pathways to glioblastomas

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Abstract
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.