Developing Patterns Templates/Db Alpha

RESEARCH HIGHLIGHTS

DOI: EXPRESSION PROFILING 10.1038/nrc1895

URL: Glioma Developing patterns http://www.cancer.gov/ Templates/db_alpha. aspx?CdrID=45700 Gliomas are currently diagnosed subtypes showed features of tumour highly significant predictive model of PTEN using histopathological criteria; the cell proliferation or angiogenesis survival in high-grade astrocytoma. http://www.ncbi.nlm.nih.gov/ main prognostic factors are tumour that were almost absent from the These findings are intriguing, as both entrez/query.fcgi?db=gene&c md=Retrieve&dopt=full_ grade and age of the patient. There better-prognosis proneural subtype. the Notch and AKT pathways have report&list_uids=5728 is now some evidence that gliomas In addition, although poor-prognosis been implicated as key regulators in might arise from neural-stem-like subtypes expressed markers of neurogenesis. EGFR http://www.ncbi.nlm.nih.gov/ cells, so Heidi Phillips and col- undifferentiated neural stem cells The authors propose a model entrez/query.fcgi?db=gene&c leagues set out to define the pattern and/or transit amplifying cells (pro- for human gliomas in which all md=Retrieve&dopt=full_ report&list_uids=1956 of disease progression in gliomas in genitor cells), the proneural subtype molecularly defined subtypes arise relation to stages of neurogenesis, expressed markers of neuroblasts or from cell types of similar origin, but DLL3 and to establish molecular-signature neurons. At the genomic level, most that differential activation of signal- http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=gene&c prognostic models. of the proliferative and mesenchymal ling pathways leads some tumours to md=Retrieve&dopt=full_ First, the authors profiled 76 tumours had losses on chromo- maintain more undifferentiated neu- report&list_uids=10683 samples from newly diagnosed cases some 10, which includes the PTEN ral-stem-cell-like or transit-amplify- of anaplastic astrocytoma and gliob- (phosphatase and tensin homologue) ing-cell-like phenotypes, whereas lastoma using microarrays. Three locus, and gains on chromosome 7, others adopt a phenotype closer clusters of tumour samples were which contains the EGFR (epider- to that of neuroblasts or immature identified with differential expression mal-growth-factor receptor) locus, neurons. Further confirmation of the of 108 survival-related genes — 35 whereas proneural tumours did not correlation between stem-cell biology of which were robust markers of the have these alterations. Notch pathway and glioma aggressiveness should three tumour subtypes. One subtype elements, including DLL3, were produce a useful molecular signature was found to express genes associated overexpressed in proneural tumours. prognostic model. with the normal brain and the process The authors then investigated Ezzie Hutchinson of neurogenesis (known as the prone- whether the phenotypes associated ural subtype), another expressed with changes in the Notch pathway ORIGINAL RESEARCH PAPER Phillips, H. et al. Molecular subclasses of high-grade gliomas proliferation-associated genes (the and the AKT pathway (which is predict prognosis, delineate a pattern of disease proliferative subtype) and a third sub- activated by changes in PTEN and progression, and resemble stages in type expressed genes associated with EGFR) were directly associated with neurogenesis. Cancer Cell 9, 157–173 (2006) angiogenesis and mesenchymal origin patient survival, and found that levels (the mesenchymal subtype). Patients of PTEN and DLL3 mRNA formed a 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 recur- rence 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