INTRODUCTION — Gliomas are primary brain tumors that display histologic features of glial cells (ie, astrocytes, oligodendrocytes, and ependymal cells). The diffuse gliomas are the most common types and generally affect the cerebral hemispheres of adults. They are classified based upon their line of differentiation and are graded according to their histologic degree of malignancy.
Diffuse gliomas in adults are classified according to the World Health Organization (WHO) system by both histologic and molecular characteristics as isocitrate dehydrogenase (IDH)-mutant or IDH-wildtype astrocytomas; IDH-mutant and 1p/19q-codeleted oligodendrogliomas; and IDH-wildtype glioblastomas [1,2]. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)
The pathogenesis and biology of diffuse gliomas are reviewed here. The pathologic diagnosis, clinical manifestations, diagnosis, and treatment of these tumors are discussed separately. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors" and "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas" and "Radiation therapy for high-grade gliomas" and "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults".)
CELL OF ORIGIN — High-grade gliomas likely arise from neural progenitor cells, but the precise stage of differentiation of such target cells (ie, stem cells versus progenitor cells) has not been clear. In isocitrate dehydrogenase (IDH)-wildtype glioblastoma, mouse models and molecular genetic studies of patient tumor tissue, adjacent subventricular zone (SVZ) biopsies, and normal tissue suggest that astrocyte-like neural stem cells in the SVZ, which contain low-level somatic driver mutations, are the cell of origin [3]. Over time these cells may migrate and acquire additional somatic mutations, ultimately leading to the development of IDH-wildtype glioblastoma in distant brain regions.
High-grade gliomas contain multipotent tumor stem cells that are responsible for populating and repopulating the tumors [4-7]. The existence of these tumor stem cells may have therapeutic implications, since therapies that do not ablate the tumor stem cells will be ineffective in eradicating the tumor.
ADULT DIFFUSE GLIOMAS — Understanding of the molecular genetic basis of high-grade gliomas has increased markedly over the last three decades [8-11]. This knowledge has provided insight into the biologic basis of high-grade glioma formation and progression. This information has permitted the generation of novel genetically engineered murine models of diffuse high-grade glioma [12-14]. Some of these molecular changes may represent potential targets for future gene or molecular pharmacologic therapies. However, single-agent therapeutic approaches may be confounded by the sometimes remarkable heterogeneity within individual high-grade gliomas, which has been demonstrated at the regional, cellular, and molecular levels [15-17].
As with other human cancers, the formation and progression of diffuse gliomas is accompanied by activation of oncogenes, inactivation of tumor suppressor genes, abrogation of apoptotic genes, and deregulation of DNA repair genes, as well as extensive epigenetic alterations. Different constellations of genetic alterations are associated with specific types of high-grade gliomas, with particular tumor grades, and with differential sensitivities to specific therapies [18].
Formation of astrocytoma — The formation of World Health Organization (WHO) grade II astrocytoma is associated with at least three moderately common genetic alterations: heterozygous point mutations in isocitrate dehydrogenase 1 (IDH1) or less commonly IDH2; mutations in the chromatin regulator gene, ATRX; and inactivation of the TP53 tumor suppressor gene (table 1).
Isocitrate dehydrogenase (IDH) gene — Somatic mutations affecting the active site of the Krebs cycle enzyme IDH1 were first identified in glioma in 2008 as part of a genomic analysis of human glioblastoma tumor samples, in which 18 out of 149 tumors (12 percent) contained alterations in IDH1, primarily at the R132 residue [19]. Subsequent studies have confirmed these findings, identified rarer mutations in IDH1 and the related gene IDH2 in glioma, and extended the spectrum of involved tumors to include a much greater proportion of lower-grade gliomas than glioblastoma [20]. Such mutations are the earliest known events in diffuse gliomagenesis [19,21].
A number of putative mechanisms have been suggested for IDH dysregulation in glioma formation:
●Heterozygous mutations in IDH1 foster the formation of an oncogenic metabolite, R(-)-2-hydroxyglutarate (2HG) [22].
•In leukemias, IDH mutation and 2HG production have been linked via DNA methylation changes to impaired hematopoietic cell differentiation [23]. Similarly, in IDH-mutant gliomas, epigenetic dysregulation mediated by 2HG results in a CpG island methylator phenotype [24,25]. The functional importance of this phenotype in early glioma formation may relate in part to changes in insulator protein binding, resulting in aberrant activation of oncogenes such as platelet-derived growth factor receptor alpha (PDGFRA) [26].
•2HG accumulation has paracrine effects on T cells in the glioma microenvironment, which may alter T cell activation and impair host antitumor immunity [27].
●IDH1 mutant enzymes may act as dominant-negative inhibitors of wildtype IDH1 enzymatic function, exerting a tumorigenic effect through induction of the hypoxia-inducible factor 1 (HIF-1) alpha pathway [28].
IDH1 or IDH2 mutations are present in 50 to 80 percent of WHO grade II and III astrocytic and oligodendroglial tumors and secondary glioblastomas as well as approximately 5 percent of primary glioblastomas [20,29]. IDH1/2 mutations in glioma are associated with significantly prolonged progression-free and overall survival compared with comparable tumors without an IDH mutation [30-33]. (See "Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas" and "Treatment and prognosis of IDH-mutant astrocytomas in adults", section on 'Prognosis'.)
The presence of IDH mutations also appears to be useful for distinguishing diffuse astrocytoma from reactive astrocytosis (gliosis), particularly in biopsy specimens. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'IDH1/IDH2 mutation'.)
Targeted inhibitors of mutant IDH1 are in development, having shown evidence of delayed growth and promotion of cell differentiation in glioma cell lines [34]. A mutation-specific vaccine is also under investigation [35].
ATRX gene — Mutations in the chromatin regulator gene, alpha-thalassemia/mental retardation syndrome X-linked (ATRX), are a novel candidate marker for astrocytic lineage in diffuse gliomas.
Missense mutations in ATRX are present in approximately 70 percent of WHO grade II and III astrocytomas [20,36-38]. ATRX is a switch/sucrose nonfermentable (SWI/SNF) helicase that plays a key role in assisting H3.3 chromatin deposition in telomeric regions, and ATRX mutations show a close correlation with an alternative lengthening of telomeres (ALT) phenotype [39]. Mutations likely represent an early event in gliomagenesis, providing a genetic mechanism responsible for telomere maintenance.
ATRX mutations are closely correlated with IDH1/2 and TP53 mutations and are mutually exclusive with 1p/19q codeletion, the molecular hallmark of oligodendroglioma [10,36-38].
TP53 gene — Early involvement of the tumor suppressor TP53 in astrocytomas has been known for decades and confirmed by next-generation sequencing studies.
TP53 maps to chromosome 17p and it encodes the p53 protein, which has an integral role in a number of cellular processes, including cell cycle arrest, response to DNA damage, and apoptosis. Inactivation of the TP53 gene, usually due to mutation of one copy and chromosomal loss of the remaining allele, occurs in approximately one-half of astrocytomas, approximately one-third of anaplastic astrocytomas and glioblastomas [9,40], and the large majority of such tumors that also harbor IDH mutations [20].
The TP53 mutations are primarily missense mutations and target the evolutionarily conserved domains in exons 5, 7, and 8. Particular mutational hot spots include codons 175, 248, and 273, in which C to T transitions are most likely the result of spontaneous deamination of 5-methylcytosine residues. These mutations affect p53 residues that are crucial for DNA binding, presumably leading to loss of p53-mediated function [18].
TP53 also plays a role in protecting cells from DNA damage. Mutations of TP53 may therefore lead to tumor progression through genomic instability [18].
Formation of oligodendroglial tumors — Simultaneous loss of chromosomes 1p and 19q is a defining molecular feature of oligodendrogliomas, presumably on the basis of a single translocation event [41,42]. Loss of 1p/19q occurs in the setting of IDH1/2 mutation, suggesting that the chromosomal losses follow the IDH1/2 mutations.
The frequent codeletion of 1p and 19q in oligodendroglioma has suggested that these chromosomal arms may contain tumor suppressor genes, and several candidate genes have been identified. Mutations of the capicua transcriptional repressor (CIC) gene on chromosome 19q13.2 have been found in 70 percent of oligodendrogliomas with 1p/19q codeletion, particularly in those with IDH mutations [36,43,44], but the functional significance of mutations in this gene remains unclear. Similarly, mutations in far upstream element binding protein 1 (FUBP1) on chromosome 1p have been observed in some oligodendrogliomas, although at a lower frequency than CIC alterations.
Telomere expression may also play a role in the pathogenesis of oligodendroglioma, but in a manner distinct from the ATRX pathway that has been implicated in astrocytoma. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter are present in the great majority of oligodendrogliomas, leading to increased telomerase expression [45,46].
Transition to high-grade glioma — The transition from low-grade to anaplastic glioma is associated with a variety of molecular alterations, including cell cycle checkpoint inactivation, tumor suppressor gene inactivation, and angiogenesis. Early molecular alterations, including IDH1/2 mutations, tend to be retained at progression, and a subset of tumors treated with alkylating chemotherapy develop a hypermutation phenotype [47,48].
Checkpoint alterations — Loss of chromosome 13q, which includes the retinoblastoma (RB) gene locus, occurs in approximately one-third of higher-grade astrocytic tumors [18].
One of the major pathways controlling the G1-S phase cell cycle checkpoint involves the p16, cyclin dependent kinase (CDK)-4, cyclin D, and pRB (retinoblastoma) proteins [18]. Alterations of at least one component of this pathway occur in many anaplastic astrocytomas and in the vast majority of glioblastomas. The protein encoded by the RB gene, pRB, is important in cell-cycle arrest; the loss of pRB function in gliomas thereby removes an important brake on the cell cycle.
One upstream mediator of pRB function is the p16 product of the CDKN2A gene (also called p16INK4A) on chromosome 9p, a tumor suppressor inactivated in a number of human tumors. p16 inhibits the cyclin-cyclin dependent kinase complex that regulates pRB. The vast majority of glioma cell lines and two-thirds of high-grade astrocytic gliomas show homozygous deletions of chromosome 9p that include this gene. It is likely that these deletions result in loss of expression of the p16 and p14ARF transcripts from CDKN2A and the p15 transcript from the nearby CDKN2B (also called multiple tumor suppressor 2 [MTS2]), resulting in loss of multiple cell cycle control checkpoints and greater proliferation [18]. Homozygous deletion of the CDKN2A gene is a predictor of worse behavior in IDH-mutant astrocytic gliomas [49].
The cyclin dependent kinase 4 (CDK4) gene is amplified and overexpressed in 10 to 15 percent of high-grade gliomas. CDK4 itself is regulated by p16 and inactivates pRB through phosphorylation. Thus, nearly all high-grade tumors have impairments of this single critical cell cycle control pathway. It is likely as well that less profound defects in cell cycle regulation occur in lower-grade gliomas; for instance, TP53 gene mutations may affect both the G1-S and G2-M checkpoints.
In general, alterations of RB, CDKN2A and the CDK4 gene are mutually exclusive in glioblastoma [50].
PTEN inactivation — Malignant progression to glioblastoma is also associated with inactivation of the phosphatase and tensin homolog (PTEN) tumor suppressor gene on chromosome 10 [51]. Chromosome 10 loss occurs in 60 to 85 percent of glioblastomas, with approximately 25 percent of cases having PTEN mutations [52].
Growth factor amplification and overexpression — A variety of growth factors, or oncogenes, are amplified and/or overexpressed in high-grade gliomas and thus provide a growth advantage to neoplastic cells. In general, glioma cells express both the ligand growth factor and its receptor, setting up an autocrine growth-promoting loop. Some growth factors are highly expressed in low-grade as well as high-grade gliomas, whereas others are primarily overexpressed only in glioblastomas. Those involved in high-grade glioma include [18]:
●Platelet-derived growth factor (PDGF)
●Epidermal growth factor receptor (EGFR)
●Met proto-oncogene/hepatocyte growth factor receptor (MET)
●Basic fibroblast growth factor (bFGF, FGF-2) and fibroblast growth factor receptors (FGFR1, FGFR3)
●Transforming growth factor (TGF)-alpha
●Insulin-like growth factor (IGF)-1
Of these, EGFR and PDGF have been most studied. Amplification of the EGFR gene is associated with progression from lower-grade astrocytoma to glioblastoma. Amplification is found in approximately 40 percent of all glioblastomas (less commonly in anaplastic astrocytomas), resulting in overexpression of EGFR, a transmembrane receptor tyrosine kinase [40]. Approximately one-third of glioblastomas with EGFR gene amplification also have gene rearrangements, some encoding truncated, constitutively active mutants; by far the most common of these is known as variant III (vIII) [18].
Rarer examples of an oncogenic chromosomal translocation fusing the tyrosine kinase coding domains of FGFR1 or FGFR3 to transforming acidic coiled-coil 1 or 3 (TACC1/3), mutually exclusive with EGFR, PDGFR, or MET amplification, suggest a novel mechanism of aberrant signaling in glioblastoma [53,54].
The wingless (WNT) signaling pathway may also be aberrant in glioblastoma, possibly playing a role in glioblastoma stem-like cell self-renewal [55]. Aberrant WNT pathway signaling is also implicated in a subset of medulloblastomas. (See "Histopathology, genetics, and molecular groups of medulloblastoma", section on 'Wnt pathway'.)
The potential therapeutic implications of these and other changes in glioblastoma are the subject of ongoing investigation.
Angiogenesis — A dramatic sequence of vascular changes occurs in the transition from anaplastic astrocytoma to glioblastoma, a fact that is reflected in the intense, almost ring-like contrast enhancement that surrounds rapidly growing tumors [56]. High-grade gliomas are highly vascular tumors, and the histologic presence of microvascular proliferation indicates that the tumor is of high grade. Angiogenic molecules have been found in high-grade gliomas, primarily in glioblastomas [9,56]. The most clearly implicated is vascular endothelial growth factor (VEGF), an endothelial cell mitogen that is expressed most often adjacent to areas of necrosis but not in grade II astrocytomas. This suggests that the malignant progression from low-grade astrocytoma to glioblastoma includes an "angiogenic switch."
VEGF receptors are expressed by tumor endothelial cells, setting up a paracrine loop in which the tumor cells encourage vascular proliferation. The microenvironment is thus of importance in glioblastoma, with regions of neovascularization often surrounding zones of necrosis. Other proangiogenic signal transduction pathways are also upregulated in glioblastoma, including PDGF and its receptor on endothelial cells, PDGFR-beta; angiopoietin-2 and its receptor Tie-2; the family of fibroblast growth factors and receptors; and stromal-cell derived factor-one alpha.
One of the main triggers for tumor-related angiogenesis is believed to be the physiologic response to hypoxia, which induces increased transcription of the VEGF gene by the hypoxia-inducible factor (HIF) family of transcription factors [57-59]. An intriguing hypothesis suggests that thrombosis of small blood vessels, perhaps mediated by tissue factor, induces micronecrosis and that these events initiate the hypoxic and angiogenic cascades [57,58]. (See "Overview of angiogenesis inhibitors".)
Treatment effects and hypermutation phenotype — Many gliomas treated with alkylating agent chemotherapy develop additional genetic alterations, termed a hypermutation phenotype. One mechanism for such hypermutation is inactivation of mismatch repair (MMR) genes [48,60,61].
A hypermutation phenotype in recurrent gliomas has been described in approximately one-quarter to one-half of recurrent gliomas with prior exposure to temozolomide chemotherapy [62-65]. The phenotype appears to be much less common after exposure to nitrosoureas or radiation alone. Among diffuse glioma subtypes, IDH-mutant gliomas and those with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation have the highest rates of treatment-associated hypermutation [47,64]. There are conflicting data on whether the presence of a hypermutation phenotype in recurrent gliomas has an adverse impact on overall survival.
Genetic subsets of glioblastoma — Adult glioblastoma is characterized by a complex genetic landscape, and genetic differences can be used to subdivide these tumors into more homogeneous groups (table 1). The current WHO classification divides glioblastomas into those that are IDH-wildtype, IDH-mutant, or not otherwise specified [66]; however, it is possible that the definition of glioblastoma in the future will be restricted to IDH-wildtype tumors [67].
Primary versus secondary glioblastoma — Secondary glioblastomas tend to occur in significantly younger adults and involve progression from a lower-grade astrocytoma. This pathway is characterized by genetic alterations in IDH1/2, ATRX, and TP53.
Primary or de novo glioblastomas most often arise in older adults who do not have a history of prior lower-grade astrocytoma; these tumors are typically characterized by receptor tyrosine kinase amplifications and TERT promoter mutations [68-70], among other genetic alterations.
Hypermethylation phenotype — CpG island methylator phenotype may also provide another means to characterize glioblastomas. Analysis of tissue from a glioblastoma tumor tissue database identified a subset of tumors that were characterized by promoter hypermethylation at a large number of loci [24]. Tumors containing this promoter hypermethylation were more commonly low grade and were observed in younger patients. These tumors were associated with IDH1 mutations and a better prognosis compared with those without the hypermethylation phenotype [30,31]. (See 'Formation of astrocytoma' above.)
Gene expression profile subtypes — Integrated analyses of gene expression profiles from large databases suggest that glioblastomas can be divided into proneural, neural, classical, and mesenchymal subtypes [71]. To date, however, studies of genetic subsets of glioblastoma have revealed a few associations, but no clear clinically relevant correlations of genotype with tumor behavior [72]. Moreover, single-cell analyses have shown that most glioblastomas have mixtures of cells, with mixed populations featuring many of these subtypes [14].
PEDIATRIC DIFFUSE GLIOMAS — Significant insights into the molecular genetics of pediatric gliomas, as distinct from adult gliomas, have been gained through whole-genome sequencing studies of pediatric tumor specimens [73].
Lower-grade astrocytoma — Despite similar histopathology, adult and pediatric diffuse gliomas have different underlying genetic events (table 1). Most strikingly, the majority of pediatric gliomas have only a single somatic event affecting protein coding sequences, suggesting that they rely on few oncogenic events.
Duplication of the tyrosine kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene is present in approximately one quarter of pediatric diffuse gliomas [73]. This duplication results in FGFR1 autophosphorylation and activation of downstream phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK/ERK) pathways. FGFR1 is also subject to other genetic events at lower frequency, including FGFR1-TACC1 and FGFR3-TACC3 translocations, which have also been reported in rare cases of adult glioblastoma [53,54].
Additional genetic changes that have been observed in pediatric low grade gliomas include rearrangements or amplifications affecting MYB or MYBL1, a variety of RAF pathway abnormalities, including BRAF fusions, and recurrent genetic events affecting histones and chromatin regulators [74]. (See "Uncommon brain tumors", section on 'Pilocytic astrocytoma' and "Diffuse intrinsic pontine glioma", section on 'Molecular pathogenesis'.)
BRAF V600E point mutations, initially described in malignant melanoma, are commonly identified in lower-grade, circumscribed (ie, not “diffuse”) gliomas, including ganglioglioma, pleomorphic xanthoastrocytoma, and extra-cerebellar pilocytic astrocytoma. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Key molecular diagnostic tests'.)
Oligodendroglioma — Pediatric oligodendroglial tumors are rare. Although few have been studied extensively, the hallmark alterations of adult oligodendrogliomas (eg, IDH1/2 mutation and 1p/19q loss) do not appear to be drivers of these lesions [75].
High-grade glioma — Pediatric glioblastomas also appear to have genetic alterations that are distinct from those observed in adult glioblastoma.
Recurrent mutations in the H3F3A gene encoding histone H3.3 have been identified in approximately 30 percent of pediatric glioblastoma samples [76,77]. Specific point mutations observed in this setting include K27M, G34R, and G34V. Mutations in the ATRX-DAXX complex, which mediates deposition of H3.3 in telomeric regions, were also identified in approximately 30 percent of these tumors [76]. Subsequent studies have highlighted that distinct H3F3A mutations define epigenetic and clinicopathologic entities and are mutually exclusive with IDH1 mutations [78].
Pediatric diffuse intrinsic pontine gliomas also commonly harbor H3 K27M mutations in either H3F3A or HIST3BHI, two of several genes encoding histone H3.1, as well as activating mutations in ACVR1. In the World Health Organization (WHO) classification, diffuse glial tumors of the brainstem, thalamus, or spinal cord with histone H3 K27M mutations are now termed "diffuse midline gliomas, H3 K27M-mutant." On the other hand, tumors with H3 G34 mutations are more often in the hemispheres of children and younger adults. (See "Diffuse intrinsic pontine glioma", section on 'Molecular pathogenesis'.)
SUMMARY
●Gliomas are primary brain tumors that display histologic features of glial cells. Diffuse gliomas are classified according to the 2016 World Health Organization (WHO) system by both histologic and molecular characteristics as isocitrate dehydrogenase (IDH)-mutant astrocytomas, IDH-wildtype astrocytomas, IDH-mutant and 1p/19q-codeleted oligodendrogliomas, as well as IDH-wildtype and IDH-mutant glioblastomas.
●The formation of WHO grade II astrocytoma is associated with at least three moderately common and sometimes definitional genetic alterations: heterozygous point mutations in isocitrate dehydrogenase 1 (IDH1) or less commonly IDH2; mutations in the chromatin regulator gene, ATRX; and inactivation of the TP53 tumor suppressor gene. (See 'TP53 gene' above and 'Isocitrate dehydrogenase (IDH) gene' above and 'ATRX gene' above.)
●The hallmark genetic aberration in oligodendroglial tumors is codeletion of chromosomal arms 1p and 19q, present in the majority of pure oligodendrogliomas. Together with mutations in IDH1/2, 1p/19q codeletion likely represents an early event in tumorigenesis. Tumor suppressor genes identified on the missing chromosomal arms include the capicua transcriptional repressor (CIC) gene on chromosome 19q and far upstream element binding protein 1 (FUBP1) on chromosome 1p. (See 'Formation of oligodendroglial tumors' above.)
●Multiple tumorigenic events are involved in the development of high-grade gliomas such as glioblastoma, including loss of cell cycle control, dysregulation of apoptosis, growth factor overexpression, and angiogenesis via both genetic and epigenetic aberrations. Alkylating agent chemotherapy induces a hypermutation phenotype in glioblastomas, at least partly as a result of defects in mismatch repair. (See 'Transition to high-grade glioma' above.)
●A variety of constructs have been proposed to subdivide glioblastoma into more homogeneous clinical and molecular groups. Primary or de novo glioblastoma refers to tumors that typically occur in older patients who do not have a history of a preceding lower-grade glioma, often characterized by receptor tyrosine kinase amplification and telomerase reverse transcriptase (TERT) promoter mutations. By contrast, secondary glioblastomas occur in younger patients, commonly progress from lower-grade gliomas, and are often characterized by early mutations in IDH1/2, ATRX, and TP53, as well as a hypermethylation phenotype. (See 'Genetic subsets of glioblastoma' above.)
●Whole-genome sequencing efforts have revealed that pediatric gliomas are genetically distinct from their adult counterparts, despite similar histopathology. In pediatric low-grade astrocytomas, duplication of the tyrosine kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene has been identified in approximately one-quarter of tumors, leading to downstream pathway activation. In pediatric glioblastoma as well as diffuse intrinsic pontine glioma, recurrent mutations in genes affecting histones and chromatin regulators have been identified in a significant minority of tumors that appear to be important pathogenic events. Those with histone H3 K27M mutations in the brainstem, thalamus, and spinal cord are referred to as "diffuse midline glioma, H3 K27M-mutant." (See 'Pediatric diffuse gliomas' above.)
