Non-GCIMP Glioblastomas Arise from a Common Proneural Precursor Cell

Glioblastoma can be divided into proneural, mesenchymal, classical, and neural tumor subtypes, which are characterized by different canonical cancer gene mutations. However, in some cases, multiple subclasses are observed within a single tumor, prompting Ozawa, Riester, and colleagues to investigate the temporal genomic evolution of glioblastoma and whether different tumor subtypes evolve via distinct mechanisms or from a common precursor. Analysis of tumor sequencing databases revealed that all glioblastoma subtypes, except those that harbor the glioma-CpG island methylator phenotype (GCIMP), shared broad chromosomal gains and losses, the most frequent of which included balanced gain of chromosome 7 and hemizygous loss of chromosome 10. Computational modeling of the evolution of genetic alterations in glioblastoma showed that gain of chromosome 7 and loss of chromosome 10 represented early steps in the development of all glioblastoma subtypes and were followed by CDKN2A loss and TP53 mutations, whereas later events such as NF1 loss were associated specifically with mesenchymal tumors. Computational ranking of genes based on expression and correlation with patient survival in proneural glioblastoma highlighted PDGFA and PTEN as primary drivers of chromosome 7 and 10 nondisjunction events, respectively. In support of this idea, exogenous expression of PDGFA was sufficient to initiate proneural-like glioblastoma formation in mice, and concomitant loss of Pten, Cdkn2a, or Trp53 increased tumor grade and shortened overall lifespan. In line with mathematical predictions, loss of Nf1 and Trp53 induced glioblastoma with mesenchymal characteristics. Building on the finding that all glioblastoma subtypes share early genomic events, depletion of Nf1 in proneural glioblastoma cells induced a shift toward a mesenchymal gene expression pattern both in vitro and in vivo. Together, these findings provide insight into the order of genetic alterations in glioblastoma evolution and suggest that most non-GCIMP mesenchymal glioblastomas arise from a proneural precursor cell.

Ozawa T, Riester M, Cheng YK, Huse JT, Squatrito M, Helmy K, et al. Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma. Cancer Cell 2014;26:288–300.