Abstract 936: Comprehensive and integrative genomic characterization of diffuse lower grade gliomas
Authors: Verhaak Roel G.W. , Cooper Lee A.D. , Salama Sofie S. , Aldape Kenneth , Yung W.K. Alfred , Brat Daniel J. 
Published: May 2015

Abstract
Background
Diffuse lower grade gliomas (LGGs) are infiltrative neoplasms of the central nervous system that include astrocytoma, oligodendroglioma and oligo-astrocytoma histologies of grades II and III. We present a comprehensive analysis of 293 LGGs using multiple advanced genomic, transcriptomic and proteomic platforms from The Cancer Genome Atlas to provide a deeper understanding of the molecular features of this group of neoplasms, to classify them in a clinically-relevant manner, and to provide a public resource that identifies potential targets for emerging therapies.
Results
Clustering of gene expression, miRNA expression, protein expression, DNA methylation and DNA copy number profiles identified respectively four, four, four, five and three clusters. When combined, the clustering results overwhelmingly pointed towards a natural grouping of LGG into three superclusters, which can be explained as follows: 1. IDH1/IDH2 wildtype 2. IDH1/IDH2 mutant and chromosome arms 1p/19q intact 3. IDH1/IDH2 mutant and co-deletion of chromosome arms 1p/19q. The three groups all included samples from grade II and III astro-, oligo- and oligo-astrocytoma histologies. Based on this result we evaluated genomic alterations according to these three LGG categories.
The IDH wildtype subtype was characterized by a GBM like phenotype, included focal gains of EGFR, CDK4 and MDM4, mutations in NF1, EGFR and PTEN, and a GBM like poor median outcome of 18 months. Approximately 55% of these cases were grade III (anaplastic) astrocytomas, while the remainder were from a mixed grade and histology. The IDH mutant/1p-19q intact group showed focal amplification of PDGFRA, MYC and CCND2, 100 % mutated TP53 and 80% with mutations in ATRX. This group was not dominated by a single grade or histology, but represented all types. Finally, the IDH mutant and 1p/19q co-deleted subtype harbored frequent mutations in CIC, FUBP1, NOTCH1, TERT, relatively few copy number alterations and was populated for 84% by oligodendrogliomas. The two IDH mutant groups associated with a favorable median survival of 90 months.
Discussion
Based on integrated analysis of genome, transcriptome, methylome and proteome we showed that LGG naturally separates into three distinct groups that traversed grades and histologies. Importantly, we identified a subtype with an LGG-like histology but a molecular GBM profile, suggesting that the GBM standard of care, concomitant radiotherapy and temozolomide, may be warranted for these patients. We propose that classification of LGG should be revised based on IDH1/IDH2 mutation and 1p/19q deletion status.
Citation Format: Roel G.W. Verhaak, Lee A.D. Cooper, Sofie S. Salama, Kenneth Aldape, W.K. Alfred Yung, Daniel J. Brat. Comprehensive and integrative genomic characterization of diffuse lower grade gliomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 936. doi:10.1158/1538-7445.AM2014-936