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Cancer Cell. 2014 Aug 11;26(2):288-300. doi: 10.1016/j.ccr.2014.06.005.

Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma.

Author information

1
Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Department of Neurosurgery and Alvord Brain Tumor Center, University of Washington, Seattle, WA 98109, USA.
2
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA.
3
Department of Pathology and Human Oncology, Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
4
Cancer Cell Biology Programme, Spanish National Cancer Research Centre, Madrid 28029, Spain.
5
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
6
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA. Electronic address: michor@jimmy.harvard.edu.
7
Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Department of Neurosurgery and Alvord Brain Tumor Center, University of Washington, Seattle, WA 98109, USA. Electronic address: eholland@fhcrc.org.

Abstract

To understand the relationships between the non-GCIMP glioblastoma (GBM) subgroups, we performed mathematical modeling to predict the temporal sequence of driver events during tumorigenesis. The most common order of evolutionary events is 1) chromosome (chr) 7 gain and chr10 loss, followed by 2) CDKN2A loss and/or TP53 mutation, and 3) alterations canonical for specific subtypes. We then developed a computational methodology to identify drivers of broad copy number changes, identifying PDGFA (chr7) and PTEN (chr10) as driving initial nondisjunction events. These predictions were validated using mouse modeling, showing that PDGFA is sufficient to induce proneural-like gliomas and that additional NF1 loss converts proneural to the mesenchymal subtype. Our findings suggest that most non-GCIMP mesenchymal GBMs arise as, and evolve from, a proneural-like precursor.

PMID:
25117714
PMCID:
PMC4143139
DOI:
10.1016/j.ccr.2014.06.005
[Indexed for MEDLINE]
Free PMC Article

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