Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma

Abstract

SUMMARY 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-wildtype diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…These studies, applying genome-wide DNA methylation profiling in an adult patient cohort, led to the identification of a G-CIMP positive group associated with isocitrate dehydrogenase 1 (IDH1) mutations, and hypermethylation at a large number of loci was linked to a less severe outcome. 47,48 Applied genomewide DNA methylation profiling in cohorts of pediatric and adult patients also described recurrent age-specific mutations in H3F3A, while tumors enriched for PDGFRA alterations occur in patients from a wider age range. 29 These techniques also led to subgrouping DIPG patients based on CpG island methylation, identifying a subgroup with high-level amplification of MYCN and high-grade histology, in which targeting histones would be irrelevant.…”

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

“…Importantly, they have been shown to be clonal mutations in gliomas (11) and are likely to play a role in tumor initiation (12). Using clonal pTERT mutations as the defining characteristic of a GBM tumor cell, we established a convenient PCR-based assay to systematically study clinical and molecular consequences of varying tumor purity.…”

Correlation between molecular features and genetic subtypes of Glioblastoma: critical analysis in 109 cases

“…17 The results we obtained, regarding the percentage of each GBM subtype, as well as their association with patient overall survival, is in accordance with what has been published so far. [5][6][7][8][9] Since the first documentation of the molecular subclasses of GBMs (available by 2010), these have proved…”

“…[4][5][6][7][8][9][10] Their potential to aid the choice of better treatment options is a step forward toward precision medicine.…”

“…GBM has been one of the most molecularly profiled tumors by several groups, including The Cancer Genome Atlas (TCGA) Networks. [4][5][6][7][8][9][10] These studies have singled out specific determinant mutations within the newly identified subtypes: proneural, neural, classical and mesenchymal. Proneural tumors present alterations customized panel included genes such as NF1, RB1, EGFR, TP53, PTEN, IDH1 and PDGFRA, whose alterations have all been previously associated with the three main GBM subtypes: proneural, classical and mesenchymal.…”