Emerging insights into the molecular and cellular basis of glioblastoma

Abstract

Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that "glioblastoma" represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.

Figure 1.

Genomic alterations underlying gliomagenesis. Both primary and secondary glioblastomas arise from precursor cells that may be distinct. Primary glioblastomas arise de novo and exhibit p53 and Rb pathway dysfunction as well as RTK/Ras/PI3K signaling dysregulation, leading to tumors that arise in older patients with a worse prognosis, likely owing to the predominant wild-type IDH1 genotype. In contrast, secondary glioblastomas are preceded by lower-grade II lesions, which progress either through grade III lesions or directly to glioblastoma. These tumors occur in younger patients and are dominated by a mutant IDH1 genotype that confers a better prognosis and is associated with a more restricted frontal lobe location.

Figure 2.

Molecular heterogeneity in glioblastoma. (A) Immunohistochemistry for the mutant EGFR receptor EGFRvIII demonstrates a heterogeneous staining pattern within the tumor. Images from Nishikawa et al. (2004) used with permission. (B) Multicolor FISH reveals distinct subpopulations of either EGFR (red) or PDGFRA (green) amplification within a glioblastoma specimen. Images obtained from Cameron Brennan.