Molecular subclassification of diffuse gliomas: seeing order in the chaos

Diffuse gliomas such as astrocytomas and oligodendrogliomas are the most common form of intrinsic brain tumor in adults. Even within a single pathologic class, these tumors are both histologically and molecularly diverse, although not randomly so. Recent large-scale genomic analyses have revealed patterns of molecular changes within tumor subclasses that harbor distinct underlying biology, clinical prognosis, and pathogenetic routes. Stereotypical mutations in isocitrate dehydrogenase genes (IDH) have been identified in a significant proportion of high-grade gliomas and the large majority of lower-grade astrocytomas and oligodendrogliomas. While the role of IDH mutation in oncogenesis is unclear, it appears to carry a positive prognosis and is also highly associated with other prognostic markers such as MGMT methylation, loss of 1p and 19q chromosome arms, and a newly recognized CpG island methylator phenotype (G-CIMP). This constellation of positive prognostic molecular features is enriched in the transcriptionally defined Proneural glioma subclass and appears to reflect a route of pathogenesis distinct from that taken by other high-grade diffuse gliomas. Another newly discovered and frequent alteration in glioma, deletion or mutation of the NF1 gene, is strongly correlated with the Mesenchymal transcriptomal signature associated with highly aggressive gliomas. Thus, while the unprecedented level of newly available molecular profiling data may seem at first to needlessly balkanize and complicate glioma subclassification, these analyses are in fact providing a more unified picture of key pathogenetic routes and potential avenues for therapeutic intervention. © 2011 Wiley-Liss, Inc.