Abstract
Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
Highlights
Diffuse gliomas represent 80% of malignant brain tumors (Schwartzbaum et al, 2006)
Histopathologic classification is well established and is the basis of the World Health Organization (WHO) classification of CNS tumors (Louis et al, 2007), it suffers from high intra- and inter-observer variability, among grade II-III tumors
Recent molecular characterization studies have benefited from the availability of the datasets generated by The Cancer Genome Atlas (TCGA) (Brennan et al, 2013; Eckel-Passow et al, 2015; Frattini et al, 2013; Kim et al, 2015; Suzuki et al, 2015; Cancer Genome Atlas Research Network et al, 2015) and have related genetic, gene expression, and DNA methylation signatures with prognosis (Noushmehr et al, 2010; Sturm et al, 2012; Verhaak et al, 2010)
Summary
Diffuse gliomas represent 80% of malignant brain tumors (Schwartzbaum et al, 2006). Adult diffuse gliomas are classified and graded according to histological criteria (oligodendroglioma, oligoastrocytoma, astrocytoma, and glioblastoma; grade II to IV). Mutations in the isocitrate dehydrogenase genes 1 and 2 (IDH1/IDH2) define a distinct subset of glioblastoma (GBM) with a hypermethylation phenotype (G-CIMP) with favorable outcome (Noushmehr et al, 2010; Yan et al, 2009). The absence of IDH mutations in LGG marks a distinct IDH-wild-type subgroup characterized by poor, GBM-like prognosis (Eckel-Passow et al, 2015; Cancer Genome Atlas Research Network et al, 2015). Recent work by us and others has proposed classification of glioma into IDH wild-type cases, IDH mutant group carrying codeletion of chromosome arm 1p and 19q (IDH mutant-codel) and samples with euploid 1p/19q (IDH mutant-non-codel), regardless of grade and histology (EckelPassow et al, 2015; Cancer Genome Atlas Research Network et al, 2015). An improved understanding of these relationships will be necessary as we evolve toward an objective genome-based clinical classification
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