Most Human Non-GCIMP Glioblastoma Subtypes Evolve from a Common Proneural-like Precursor Glioma

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2014 Aug 14

PMID 25117714

Citations 232

Authors

Tatsuya Ozawa

Markus Riester

Yu-Kang Cheng

Jason T Huse

Massimo Squatrito

Karim Helmy

Nikki Charles

Franziska Michor

Eric C Holland

Affiliations

Soon will be listed here.

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.

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