First, the authors profiled 76 samples from newly diagnosed cases of anaplastic astrocytoma and glioblastoma using microarrays. Three clusters of tumour samples were identified with differential expression of 108 survival related genes — 35 of which were robust markers of the three tumour subtypes. One subtype was found to express genes associated with the normal brain and the process of neurogenesis (known as the proneural subtype), another expressed proliferation associated genes (the proliferative subtype) and a third subtype expressed genes associated with angiogenesis and mesenchymal origin (the mesenchymal subtype). Patients with the proneural subtype had better prognosis (median survival 174.5 weeks) than those with either the proliferation (60.5 weeks) or mesenchymal subtypes (65 weeks). Profiling of an independent set of 31 glioblastoma cases confirmed the prognostic value of this classification. The authors then compared the signatures of 26 pairs of matched specimens — primary and recurrent astrocytoma from the same patient — and found that on recurrence tumours tend to shift towards the mesenchymal phenotype.
So, what are the main features of each subtype, and how do they relate to neurogenesis? The poor prognosis subtypes showed features of tumour cell proliferation or angiogenesis that were almost absent from the better prognosis proneural subtype. In addition, although poor prognosis subtypes expressed markers of undifferentiated neural stem cells and/or transit amplifying cells (progenitor cells), the proneural subtype expressed markers of neuroblasts or neurons. At the genomic level, most of the proliferative and mesenchymal tumours had losses on chromosome 10, which includes the
PTEN
(phosphatase and tensin homologue) locus, and gains on chromosome 7, which contains the
EGFR
(epidermal growth factor receptor) locus, whereas proneural tumours did not have these alterations. Notch pathway elements, including DLL3, were overexpressed in proneural tumours. The authors then investigated whether the phenotypes associated with changes in the Notch pathway and the Akt pathway (which is activated by changes in PTEN and EGFR) were directly associated with patient survival, and found that levels of PTEN and DLL3 mRNA formed a highly significant predictive model of survival in high-grade astrocytoma. These findings are intriguing, as both the Notch and Akt pathways have been implicated as key regulators in neurogenesis.
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