Perspectives on IDH mutation in diffuse gliomas

Abstract

Isocitrate dehydrogenase (IDH) mutations are biomarkers to classify diffuse gliomas into biologically similar subgroups. Tremendous efforts have been made to understand the biology of IDH-mutant gliomas at the genetic, epigenetic, transcriptional, and protein levels. Preclinical models that recapitulate human tumor biology are crucial not only to our understanding of IDH mutations in gliomagenesis, but also in testing of novel therapeutic agents that may lead to more effective therapies for IDH-mutant glioma patients.

Isocitrate dehydrogenase 1 and 2 (IDH1/2) are commonly mutated metabolic genes in human cancers. Since 2008, when a recurrent missense mutation in IDH1 was first discovered in progressive glioblastomas [1], an enormous number of studies have been developed to characterize this genetic alteration and understand its biological impact in gliomas.

IDH mutations are frequently found in low grade gliomas (LGGs, World Health Organization Grade II and III) or secondary glioblastomas, and are much less common in primary glioblastomas. IDH mutation results in a loss of function in alpha-ketoglutarate (α-KG) production, but a gain of function to produce 2-hydroxyglutarate (2-HG), a putative oncometabolite. 2-HG was found to competitively inhibit the activities of α-KG-dependent dioxygenases, including histone demethylases and the ten-eleven translocation (TET) family of 5-methylcytosine (5mc) hydroxylases, leading to genome-wide histone and DNA methylation alterations that may contribute to tumorigenesis [2, 3].

In recent years, multiple comprehensive, multiplatform genome-wide analyses have provided valuable molecular and biological insight into IDH-mutant gliomas and identified clinically relevant subgroups based on shared genetic and epigenetic features. A TCGA analysis of newly diagnosed diffuse gliomas, including WHO grades II, III, and IV, for gene expression, DNA copy number, DNA methylation, exome sequencing, and protein expression identified six methylation groups, LGm1-6, and four transcriptome groups, LGr1-4 [4]. IDH mutation status was found to be the primary driver of methylation and transcriptome clustering, separating the cohort into two major group: LGm1-3 carried IDH mutation, was enriched for LGG, and exhibited genome-wide hypermethylation; LGm4-6 carried wildtype (WT) IDH, was enriched for glioblastoma, and exhibited less methylation genome-wide. Along with the functional copy number signature analysis, these findings confirmed that the IDH mutation status is the major determinant of the genomic landscape in diffuse gliomas. Further clustering of the IDH-mutant gliomas identified three epigenetic groups: one with loss of heterozygosity of chromosome 1p and 19q (co-del 1p/19q), consisting of IDH-mutant LGGs with oligodendroglioma histopathology; and two groups without co-del 1p/19q, consisting of both IDH-mutant LGGs and glioblastomas, but differing in glioma CpG island methylator phenotype (G-CIMP) levels, which correlated with distinct clinical outcomes. Contrary to the prevailing belief that IDH mutation is a favorable prognostic factor in glioma, this low level G-CIMP subgroup of IDH-mutant gliomas correlated with very poor prognosis compared to the same non-co-del 1p/19q, IDH-mutant gliomas with high levels of G-CIMP. In addition to epigenetic alterations, accompanying genetic mutations were commonly found in IDH-mutant LGGs with co-del1p/19q, including CIC, FUBP, PIK3CA, and NOTCH1, while TP53 mutation and inactivating alteration of ATRX were frequently observed in those without co-del 1p/19q [5]. In the latter group of patients, focal gains of 4q12, 12q14, and 8q24, loci harboring PDGFRA, CDK4, and MYC, respectively, were observed.

Although we have gained tremendous insights into IDH-mutant glioma biology, additional questions remain, such as what drives IDH-mutant gliomas to undergo higher grade transformation and gain a more aggressive, and eventually lethal, biological behavior. A genomic study comparing progressed glioma samples to their lower-grade counterparts revealed that progressed gliomas acquired more and new mutations that are different from their lower grade counterpart [6]. An amplified genomic region of MYC locus and a deleted region of CDKN2A/2B locus are commonly seen in progressed tumors, where 10q (harboring PTEN) was also frequently lost. Interestingly, a subset of IDH-mutant high grade gliomas (HGGs) develop a hypermutator phenotype (HMP), which may relate to previous chemotherapies of alkylation agents and/or radiation treatments [7]. The mechanisms of malignant transformation and HMP development remain to be elucidated. However, the investigations can be hampered by challenges in developing adequate preclinical models to mimic the IDH-mutant gliomas in patients [8].

Holmen and colleagues developed a preclinical mouse model to assess the role of IDH mutation in glioma development in the context of clinically relevant cooperating genetic alterations. Using the RCAS (replication-competant avian sarcoma-leukosis virus long terminal repeat with splice acceptor)/tumor virus A (TVA) gene delivery system, the authors introduced mutant R132H or WT IDH1 into astrocytes derived from Nestin::TVA (N::TVA);Cdkn2a^lox/lox mice and (N::TVA);Cdkn2a ^lox/lox;Atrx ^lox/lox mice. A modest increase in proliferation was seen in astrocytes from mice with Cdkn2a and Atrx loss following the introduction of mutant IDH. Additional overexpression of PDGFA in IDH1^R132H astrocytes with Cdkn2a and Atrx loss only caused a modest increase in proliferation, while a 10-fold increase in cell proliferation was observed only after Pten loss was introduced in this background, suggesting that IDH mutation promotes cell proliferation in the context of Cdkn2a, Atrx, and Pten loss and PDGFA amplification [9]. IDH mutation was found to be an early genetic event in gliomagenesis. Although many genetic alterations may co-exist in a subset of patients, the order of these accumulated genetic events may differ from the animal model created in this study. It would be interesting to know whether the biological phenotype remains consistent if the IDH mutation was introduced prior to other genetic events. Nevertheless, this model can be used to test selective sensitivity in IDH-mutant gliomas. Philip et al. found IDH1^R132H mouse astrocytes with deletion of Cdkn2a, Pten, and Atrx and overexpression of PDGFA are more sensitive to the poly(ADP-ribose) polymerase (PARP) inhibitor Olaparib compared to IDH WT cells with the same genetic background. This increased sensitivity was potentiated by temozolomide in IDH-mutant cells, but not in WT IDH-expressing cells, in concurrence with previous findings [10]. These results have provided additional rationale for targeting PARP-associated DNA repair as a novel therapeutic strategy for IDH-mutant gliomas.

The discoveries of IDH mutation in gliomas and the biology of this unique genetic event have made a great impact in the field of neuro-oncology. Through large scale multiplatform genomic studies, IDH mutation has quickly become a major biomarker to classify and understand diffuse gliomas. Preclinical models that recapitulate the tumor biology of human IDH-mutant glioma is instrumental to understand the interactions between different genetic alterations and to further test therapeutic agents and generate meaningful preclinical data for hypothesis-driven clinical trials, which may lead to an effective therapy for IDH-mutant glioma patients.

Figure 1.

Correlation of genomic features and subtypes to outcome in diffuse gliomas

*Genomic alterations discussed in this article

**A small subset of IDH-WT LGG diffuse gliomas that share epigenomic and genomic features with pilocytic astrocytoma is associated with favorable clinical outcome