Neuro-Oncology 17:v91 – v100, 2015.
doi:10.1093/neuonc/nov215.6
NEURO-ONCOLOGY
Abstracts
GENO-06. A PAN-GLIOMA CHARACTERIZATION OF
GENOMIC, EPIGENOMIC AND TRANSCRIPTOMIC ACTIVITIES
REVEALS NOVEL RELATIONSHIPS BETWEEN HISTOLOGICAL
SUBTYPES AND MOLECULAR SIGNATURES
Floris P. Barthel3, Michele Ceccarelli1,2, Tathiane M. Malta4, Thais S. Sabedot4,
Sofie R. Salama5, Stefano M. Pagnotta1, Bradley A. Murray6,
Olena Morozova5, Yulia Newton5, Daniel J. Brat7, Andrew D. Cherniack6,
Hailei Zhang6, Laila Poisson3, Lee Cooper7, Raul Rabadan8, Peter W. Laird9,
David H. Gutmann9, Houtan Noushmehr4, Antonio Iavarone8, and Roel
G.W. Verhaak3; 1Department of Science and Technology, University of
Sannio, Benevento, Italy; 2Qatar Computing Research Institute, HBKU,
Qatar, Qatar; 3Department of Genomic Medicine, Department of
Bioinformatics and Computational Biology, Department of Neuro-Oncology,
Department of Neurosurgery, Department of Pathology, University of Texas
MD Anders, Houston, TX 77030, USA; 4Department of Genetics, Ribeirão
Preto Medical School - FMRP, São Paulo, Brazil; 5UC Santa Cruz Genomics
Institute, University of California, Santa Cruz, CA, USA; 6The Eli and Edythe
L. Broad Institute of Massachusetts Institute of Technology and Harvard
University, Cambridge, MA, USA; 7Winship Cancer Institute, Emory
University, Atlanta, GA, USA; 8Department of Neurology, Department of
Pathology, Institute for Cancer Genetics, Department of Systems Biology and
Biomedical Informatics, Columbia University Medical Center, New York,
NY, USA; 9Henry Ford Hospital, Detroit, MI, USA
Although histopathologic classification of adult gliomas is well established,
Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.
accurate diagnosis suffers from high intra- and inter-observer variability. In
order to investigate the molecular underpinnings we performed an unbiased
pan-glioma analysis of molecular features. We assembled the largest possible
primary glioma dataset to date consisting of 1,122 TCGA samples of grades
II-IV glioma that have been analyzed through mRNA sequencing and expres-
sion arrays (n ¼ 1045), DNA methylation arrays (n ¼ 932), exome sequenc-
ing (n ¼ 833), DNA copy number arrays (n ¼ 1084) and whole genome
sequencing (WGS, n ¼ 141). In addition to 30 known glioma drivers like
IDH1, TP53, and EGFR, we identified 70 novel significantly mutated genes
which were mutated at 0.5-3% frequency, including KRAS, NOTCH2 and
ARID2. Novel copy number drivers included SETD2, ARID2, and GIGYF2.
Analysis of WGS data identified enrichment for mutations in the promoter
regions of TERT, CACNG6 and TRIM28 that were associated with a signifi-
cant difference in mRNA expression, suggesting functional consequences. We
used WGS based telomere length estimates and found that ATRX mutated
samples showed significantly longer telomeres while TERT mutant samples
showed shortened telomeres, independent of differences in age and IDH
status. Unsupervised clustering of DNA methylation and gene expression re-
sulted in six methylation subtypes and four expression subtypes. These clusters
overlapped significantly disregarding tumor histopathology and could be
divided into three macro groups separated by IDH mutations, TERT promoter
mutations and 1p/19q co-deletion. Functional enrichments within-cluster re-
vealed that grade IV tumors are primarily marked by a hyperproliferation sig-
nature with respect to grade II-III tumors which are characterized by increased
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activation of genes related to glial-neuronal functioning. These findings
suggest that tumor grade reflects a point in time in the temporal evolution
within individual glioma subtypes. Our analyses identified new drivers;
suggest a novel association between telomere length and maintenance mecha-
nisms and shed light on glioma evolution.