Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

Abstract

BACKGROUND Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.)

Molecular Genetics of Secondary Glioblastoma

“…In another series of 457 WHO grade II/III gliomas, 80.7% of the patients were found to harbor an IDH mutation (20). The Cancer Genome Atlas Research Network found an IDH mutation in 226 (80.1%) of 282 WHO grade II/III gliomas (21). Based on these results, the WHO now recognizes IDH mutation as a critical biomarker in the classification of gliomas (4).…”

“…Conversely, it can be argued that all GBMs harboring a WT IDH are biologically primary GBMs: cases of secondary GBM without an IDH mutation likely represent a progression from an undergraded, lower grade, or anaplastic glioma (8). These assumptions are borne out by recent data that show that gliomas lacking mutation in IDH or having chromosomal loss at 1p and 19q cluster by expression analysis and DNA copy-number profiling (21) and portend a severe prognosis (17). With an increased understanding of molecular markers and their incorporation into clinical trials, the disparity between molecular markers and histopathology-based diagnostics methods becomes more evident.…”

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

“…[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.…”

Defining neoplastic diseases differently: An emerging paradigm from The Cancer Genome Atlas lower-grade gliomas project

“…Despite widespread use, this time-honored method of histologic classification and grading suffers from well-documented inter-and intraobserver variability and does not adequately predict clinical outcomes or response to therapies. 3,4 In the Lower Grade Gliomas (LGG) project of The Cancer Genome Atlas (TCGA), 5 we attempted to determine whether biologic classes of disease with clinically distinct behaviors could be captured more cohesively and reliably by the integration of genomic profiling using multiple advanced molecular platforms. We collected nearly 300 diffuse low-grade and intermediate-grade gliomas (oligodendroglioma, astrocytoma, and oligoastrocytoma, WHO grades II and III) and analyzed them for mutations by whole-exome sequencing, DNA copy number alterations, DNA methylation, microRNA expression, and mRNA expression.…”