title: Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma.
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.
authors.affiliation: 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.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Riester
authors.affiliation: 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.
authors.forename: Yu-Kang
authors.initials: YK
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Human Oncology, Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.affiliation: Cancer Cell Biology Programme, Spanish National Cancer Research Centre, Madrid 28029, Spain.
authors.forename: Massimo
authors.initials: M
authors.lastname: Squatrito
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Karim
authors.initials: K
authors.lastname: Helmy
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nikki
authors.initials: N
authors.lastname: Charles
authors.affiliation: 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.
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.affiliation: 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.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D058674:Chromosome Duplication; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005784:Gene Amplification; D018628:Gene Dosage; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D025542:Neurofibromin 1 / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1; D020574:Proto-Oncogene Proteins c-sis; C512478:EGFR protein, human; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human