Genomic Characterization of Isocitrate Dehydrogenase-1–Mutant Glioma Malignant Progression (2016)

Over time, low-grade gliomas generally progress to become high-grade gliomas. We have learned a great deal about the development and characterization of low-grade gliomas, but we do not yet fully understand the mechanisms driving the malignant progression of these tumors. Bai et al1 systematically compared low-grade gliomas with their subsequent high-grade successors to begin answering this fundamental question. The authors obtained low-grade and subsequently high-grade glioma samples from 41 patients. The low-grade gliomas that were included all had isocitrate dehydrogenase-1 (IDH1) mutations. The authors performed whole-genome sequencing to compare exome differences and gene copy numbers. They performed gene expression profiling to compare transcriptional differences, and they used a variety of advanced methods to compare epigenetic phenomena between the low- and high-grade tumor samples. Gene sequencing redemonstrated several previously known findings such as frequent deletion of the CDKN2A tumor-suppressor locus (chromosome 9p), frequent amplification of the MYC oncogene (chromosome 8q), 1p and 19q deletions in oligodendroglial tumors, and loss of heterozygosity at the P53 locus (chromosome 17p) in astrocytic tumors. Gene sequencing also identified 3 commonly altered genes or gene families in the high-grade gliomas: (1) the receptor tyrosine kinase–renin-angiotensin system–phosphoinositide 3-kinase pathway, which includes a cell-surface receptor, a G protein, and an intracellular signal transduction enzyme; (2) the NOTCH pathway, which includes a cell-surface receptor involved in intracellular signaling; and (3) the FAT gene family, which encodes cadherin-type cell-surface receptors involved in cellular proliferation. Gene expression profiling identified several cell cycle–related transcriptional alterations that characterized high-grade gliomas but not low-grade gliomas. For example, fork-head box protein M1, which regulates cell-cycle progression from the G2 stage to the mitosis phase, and the MYC transcription factor, which increases gene expression in many cancers,2 were both frequently overexpressed in the high-grade cohort. Finally, the epigenetic profile of the high-grade tumors differed from that of their low-grade predecessors. Although methylation was relatively widespread in the low-grade cohort, epigenetic hypermethylation in the high-grade cohort was more selective and appeared to silence the transcription of genes involved specifically in cellular differentiation, reverting cells to a more stem cell–like state. It is interesting to note that although many mutations in the low-grade cohort were lost in their high-grade descendants and although many new mutations were acquired in the high-grade cohort, the IDH1 mutation was nearly perfectly conserved over time, alluding to the centrality of this mutation in glioma pathology (Figure).3 Another interesting observation is that the high-grade tumors from patients who underwent chemotherapy or radiation therapy acquired more mutations than high-grade tumors from untreated patients.Figure: Left, number of protein-altering mutations and percentage of the genome with copy number alterations (CNAs) specific to the initial or progressed tumor shown for all 41 patients. Alterations specific to progressed or initial tumors are shown in dark blue or gray, respectively. Right, recurrently mutated driver genes are labeled along the horizontal axis. The vertical axis represents mutation recurrence. Mutations are colored according to whether they are specific to the initial low-grade tumor (gray) or the progressed high-grade tumor (dark blue) or are shared by the 2 (light blue). HM, histone modification. Modified from Bai et al. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Bai H, Harmancı AS, Erson-Omay EZ, et al. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nat Genet. 2016;48(1):59-66), copyright (2016).This research highlights the incredible genetic complexity underlying glioma pathology. The broad genomic analyses performed suggest that as glioma cells become higher grade, they mutate to increase proliferation and to decrease differentiation. The authors are to be congratulated for this genomic tour de force that lays the groundwork for future research.