Gliomas are the most common CNS tumors in children and adolescents, and they show an extremely broad range of clinical behavior. The majority of pediatric gliomas present as benign, slow-growing lesions classified as grade I or II by the WHO classification of CNS tumors. These pediatric low-grade gliomas (LGGs) are fundamentally different from IDH-mutant LGGs occurring in adults, because they rarely undergo malignant transformation and show excellent overall survival under current treatment strategies. However, a significant fraction of gliomas develop over a short period of time and progress rapidly and are therefore classified as WHO grade III or IV high-grade gliomas (HGGs). Despite all therapeutic efforts, they remain largely incurable, with the most aggressive forms being lethal within months. Thus, the intentions of neurosurgeons, pediatric oncologists, and radiotherapists to improve care for pediatric patients with glioma range from increasing quality of life and preventing long-term sequelae in what is often a chronic, but rarely life-threatening disease (LGG), to uncovering effective treatment options to prolong patient survival in an almost universally fatal setting (HGG). The last decade has seen unprecedented progress in understanding the molecular biology underlying pediatric gliomas, fueling hopes to achieve both goals. Large-scale collaborative studies around the globe have cataloged genomic and epigenomic alterations in gliomas across ages, grades, and histologies. These studies have revealed biologic subgroups characterized by distinct molecular, pathologic, and clinical features, with clear relevance for patient management. In this review, we summarize hallmark discoveries that have expanded our knowledge in pediatric LGGs and HGGs, explain their role in tumor biology, and convey our current concepts on how these findings may be translated into novel therapeutic approaches.

Pediatric low-grade gliomas (LGGs) or glioneuronal tumors (WHO grade I or II) are a highly heterogeneous collection of entities accounting for 25% to 30% of all childhood CNS tumors. They are roughly as common as malignant gliomas and embryonal tumors combined.1,2 The most common single entity is pilocytic astrocytoma (PA; > 15% of tumors in patients age 0 to 19 years1), with ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), and diffuse glioma, each composing a notable minority. Some additional subsets are so rare that they are only now starting to be described.3 Overlapping morphology (eg, variants of DNET, entrapped v neoplastic ganglion cells, and microvascular tumors resembling higher-grade tumors) can pose a diagnostic challenge. Furthermore, the natural proliferative potential of the developing CNS may complicate assessments of malignancy, meaning that slightly increased mitotic indices or Ki-67 immunostaining do not automatically preclude a benign course.

In stark contrast to adult lower-grade gliomas, IDH mutations are almost absent in children, and malignant progression is extremely rare in pediatric LGGs. Outcomes are typically good, with 5-year overall survival of approximately 95% (see Stokland et al4). Thus, particularly for tumors not amenable to gross resection, LGGs often become a chronic disease, and affected children may experience a protracted reduction in quality of life.5 Although there are some reported prognostic indicators (eg, Stokland et al4), we currently know little about the mechanisms by which these tumors relapse or progress. One exception to this may be BRAF V600E mutant and 9p21 (CDKN2A/B)–deleted tumors (hallmark lesions of pleomorphic xanthoastrocytoma2), which likely display an increased propensity for progression and a worse outcome.6

Also in contrast to most adult gliomas, a notable fraction of pediatric LGGs can be linked to a hereditary component. For example, subependymal giant cell astrocytoma is closely associated with germline mutations in TSC1 or TSC2 and occurs in up to 20% of patients with tuberous sclerosis complex.7 A similar proportion of patients with neurofibromatosis type I (NF1) develop a pilocytic astrocytoma during the first decade of life, typically in the optic pathway.8 There are also links between a second RASopathy, namely Noonan syndrome, and pilocytic astrocytoma.9-11 This syndrome is often a result of germline mutations in PTPN11, which was recently found to be somatically mutated together with FGFR1 in a subset of PAs.12

Now seen as a canonical single-pathway disease, essentially 100% of PAs harbor an alteration in the MAPK axis,12,13 most commonly KIAA1549:BRAF fusion.14 A variety of additional alterations in this pathway have been identified in other LGG histologies, including additional BRAF fusions and mutations; RAF1 fusions; mutations, fusions, or kinase domain duplications of FGFR1; and fusions of the NTRK gene family.12,13,15 The link between individual alterations and particular histologies is not 100% clear, as summarized in Figure 1. Although BRAF fusions are almost exclusive to PA, BRAF V600E mutation, for example, is seen in some PAs as well as a substantial fraction of ganglioglioma and pleomorphic xanthoastrocytoma.16 One notable exception with BRAF fusions is the recently described diffuse leptomeningeal glioneuronal tumor (also known as disseminated oligodendroglioma-like leptomeningeal neoplasm), which often shows a KIAA1549:BRAF fusion together with isolated 1p or combined 1p/19q deletion.17 FGFR1 alterations also occur across histologies but with an apparent enrichment in DNETs.12,13,18,22

Thus, MAPK alterations underlie many low-grade glial/glioneuronal entities. MAPK-related oncogene-induced senescence is also likely one reason for their relatively benign behavior.19,23 However, additional signaling programs are altered in some subsets. A role for amplification and/or rearrangement of MYB/MYBL1, for example, has been identified in a proportion of LGGs, particularly with a diffuse astrocytic or angiocentric morphology.13,20,21 Although the ultimate downstream consequences are not yet fully clear, it is thought that the most common fusion event (MYB:QKI) acts through a triple mechanism of MYB truncation, increased expression through enhancer hijacking, and loss of QKI tumor suppressor function.24

The mainstay of current LGG therapy is surgical excision, which may be curative where total resection is possible. In areas where subtotal (or no) resection is possible, however, the chances of progression or relapse are substantial. Here, chemotherapy with either a vincristine plus carboplatin or vinblastine monotherapy regimen is usually given.25-27 Of note is that temozolomide, the treatment of choice for adult diffuse gliomas, is no better than standard therapy for pediatric LGG.28 Although current chemotherapies are associated with good overall survival, long-term treatment (especially over several rounds) is often associated with significant morbidity.5 A more tailored approach is therefore needed to improve quality of life.

To address issues such as translation of biologic knowledge into planning of future LGG trials, a group of scientists and clinicians recently established a consensus-finding group.29 Their recommendations noted that functional outcomes, not just survival, should be considered as key end points; that molecular analysis through resection or biopsy should be performed before adjuvant therapy, and that a combined histologic and molecular stratification should be routinely implemented to facilitate assignment to novel therapeutic studies. It is hoped that a targeted approach may deliver improvements in tumor control and in functional measures with fewer adverse effects, focusing on quality of survival rather than absolute rates. A success story in LGG is the use of mTOR inhibitors for treating subependymal giant cell astrocytoma, a safe and effective treatment which is now approved.30 On the basis of growing knowledge of activated signaling pathways in other LGGs, several early-phase clinical trials looking at MAPK-targeted therapy have recently been completed or are currently in progress.

Initial results with MEK inhibitors (MEKi), which should block pathway activity regardless of the precise upstream alteration, seem to be promising. Both selumetinib and trametinib have completed phase II trials, and plans for phase III trials are in advanced stages. Initial evidence suggests a particularly strong signal in NF1-associated tumors, which would be in keeping with recent results in NF1-associated plexiform neurofibroma.31

Studies with drugs targeting the V600E-mutant form of BRAF have also shown positive results, with at least disease stabilization seen in almost all patients in a dabrafenib study.32 Care must be taken, however, when considering treatment with these type I BRAF V600E–specific inhibitors, because some (such as sorafenib33) can show paradoxical stimulation of tumor growth in the context of the more common KIAA1549:BRAF fusion.34 The next round of early-phase trials includes both type II RAF inhibitors, which should overcome this activation,35 and BRAF inhibitor/MEKi combinations ( identifier: NCT02124772), whereas both FGFR1 and NTRK kinases represent additional possible targets. Thus, although they have a ways to go before they become standard of care, there is reason for optimism about the impact that personalized medicine may have on the survival and especially the quality of life of children with LGG.

Pediatric high-grade glioma (HGG) essentially includes anaplastic astrocytoma (WHO grade III) and glioblastoma multiforme (GBM; WHO grade IV), both malignant, diffuse, infiltrating astrocytic tumors.2 Gliomatosis cerebri, a highly infiltrative HGG manifestation affecting multiple brain regions, is thought to represent a phenotypic extreme rather than a distinct entity.36 Diffuse intrinsic pontine glioma (DIPG), a diagnosis frequently established by a combination of clinical symptoms (rapidly developing brain stem dysfunction and/or cerebrospinal fluid obstruction) and radiologic criteria (large, expansile brain stem mass occupying more than two thirds of the pons), shows a uniformly aggressive behavior, even when displaying lower-grade histology.37 This is partly reflected in the updated WHO 2016 criteria, whereby diffuse midline gliomas with K27M histone mutations (including most DIPGs) are classed as WHO grade IV, regardless of histology.2 The morphology and neuropathologic characteristics of anaplastic astrocytoma (ie, foci of increased cell density, nuclear atypia, and mitotic activity) and glioblastoma (additional microvascular proliferation and/or necrosis) usually correspond with a poorly defined tumor mass on magnetic resonance imaging. Analysis of adult glioma has shown that most IDH-wild-type grade III astrocytomas have a dismal prognosis, which mimics that of GBM,38 and the prognostic/biologic relevance of histologically distinguishing between grade III and grade IV in children is also not clear.

Pediatric HGGs may manifest across all ages and anatomic CNS compartments and are among the most common malignant CNS tumors in children. The reported age-adjusted incidence of 0.26 per 100,000 population1 is likely an underestimate, because DIPGs with low-grade histology or without histologic assessment are not assigned as HGG in epidemiologic registries, and poorly differentiated HGG variants previously may have been diagnosed as primitive neuroectodermal tumors39 or tumors with mixed ependymal, glial, or glioneuronal features. Improved profiling through methods such as DNA methylation analysis may help with the latter issue.

Phenotypically indistinguishable from the adult disease, early molecular profiling studies suggested a different biology underlying childhood HGG.40-45 International next-generation sequencing efforts shortly thereafter discovered somatic histone mutations as a hallmark of HGG in children and young adults, namely K27M and G34R/V mutations in H3.3- and H3.1-coding genes.46,47 Subsequently, numerous reports have investigated the impact of these mutations on the epigenome,48-51 and associations with other molecular,52-56 pathologic,56-59 or clinical49,60-63 features, highlighting a pivotal role in gliomagenesis. The resulting insights have formed our current concept of molecular HGG subgroups: that distinct cell-of-origin populations of the developing CNS, susceptible to specific oncogenic hits, give rise to biologically and clinically distinct groups of tumors that are likely to respond to different therapies. An overview of key alterations by location is summarized in Figure 2, and an example visualization of distinct subclasses of both LGGs and HGGs is provided in Figure 3.

The majority of pediatric diffuse midline gliomas arising in the brain stem (ie, DIPG; > 90%),61 thalamus (approximately 50%),61 and spinal cord (approximately 60%)63 harbor mutations at position 27 (K27M) in genes coding for histone 3 variants (H3F3A, approximately three fourths; HIST1H3B/C, approximately one fourth, and other rare variations).61 The K27M-mutant histone 3 protein inhibits polycomb repressive complex 2 (PRC2) activity via sequestration of its catalytic subunit EZH2,48 resulting in globally decreased H3 K27 trimethylation (H3 K27me3).50 Emerging patterns suggest further biologic diversity within K27M-mutated tumors: H3.3 mutations are found across midline structures (co-occurring with FGFR1 and/or NF1 mutations in some thalamic gliomas53), typically affect children age 7 to 10 years and are associated with very poor outcome.61 In contrast, H3.1 mutations are largely restricted to DIPG with earlier onset (age 4 to 6 years), have been associated with distinct clinicopathologic and radiologic features and a slightly better prognosis, and frequently co-occur with ACVR1 mutations.52-55,61 Initially thought to be pathognomonic for high-grade astrocytic tumors,57,66 the spectrum of CNS tumors with H3 K27M mutations has recently been expanded to include rare examples of lower-grade midline gliomas and posterior fossa ependymomas,12,13,67,68 in which their prognostic impact is yet to be defined.

Up to one third of hemispheric pediatric HGGs carry mutations at position 34 (G34R/V) in H3F3A.46,47,49,52 Although the exact consequences of H3.3 G34 mutations are not yet understood, associations with mutations in ATRX and subtelomeric hypomethylation may indicate a role for telomerase-independent telomere maintenance mechanisms (ie, alternative lengthening of telomeres) in this subset of tumors.46,49 Other molecular features include a high percentage of TP53 mutations (> 85%) and MGMT promoter methylation, which is absent from other pediatric HGG subgroups.56 G34-mutated tumors also have a divergent histopathologic appearance, with some displaying a more primitive morphology.39,56,58 However, their hemispheric-restricted location, typical manifestation during adolescence or young adulthood (age 10 to 25 years), and association with slightly prolonged survival compared with other HGGs strongly argue for a biologically uniform entity.49,56

Only a small number of HGGs in older adolescents display hotspot mutations in IDH1/2 genes, thereby representing the lower age spectrum of adult gliomas (reviewed in Sturm et al64). From the remaining heterogeneous fraction of H3/IDH-wild-type pediatric HGGs (approximately 50%), more subgroups are beginning to emerge. For example, amplifications of MYCN, often co-amplified with ID2, may drive a subset of DIPGs and supratentorial tumors with variable glioma or primitive neuroectodermal tumor–like morphology.39,54 Other subgroups are enriched for amplifications or mutations in receptor tyrosine kinase genes such as PDGFRA or EGFR.49,65,69 Initial evidence points toward possible prognostic differences in these subsets.69 Other recently detected alterations include fusions involving MET70 and NTRK1-3 genes, the latter being enriched in infant HGGs and pointing to some overlap with LGG biology in this age group.52

An estimated 5% to 10% of pediatric HGGs harbor BRAF V600E mutations. These tumors are predominantly cortical, share histologic and epigenetic characteristics with pleomorphic xanthoastrocytoma (PXA), and frequently harbor homozygous CDKN2A/B deletions.6 The slightly better clinical outcome of patients with these tumors may explain some of the long-term survivors seen in HGG clinical trials.71 More importantly, targeted therapy for this molecularly defined group of patients72-74 is currently being tested in clinical trials ( identifiers: NCT01677741 and NCT01748149). Of note, BRAF V600E mutations are also commonly encountered in epithelioid GBM, which can display histologic features similar to those of PXA but typically with a worse prognosis.75,76 The association between these two entities both clinically and biologically (eg, whether epithelioid GBM may represent a malignant transformation of PXA) is worthy of additional investigation.

A small number of pediatric HGGs are thought to result from cancer predisposition syndromes. Some GBMs arise in patients with constitutional mismatch repair deficiency (caused by homozygous mutations in mismatch repair genes PMS2, MLH1, MSH2, and MSH6), and exhibit a greatly increased mutational burden. Recent reports of responses of such tumors to immune checkpoint inhibition, likely through presenting a high load of T-cell activating neoantigens, have implications for constitutional mismatch repair deficiency–associated GBM and other HGGs with an acquired hypermutator phenotype.77

Such translational progress is urgently needed, because current treatment strategies generally bring minimal benefit. The standard therapy in diffuse midline (and therefore unresectable) gliomas is radiotherapy (and best supportive care), temporarily improving quality of life but barely increasing survival.78,79 Most patients die within 1 year after diagnosis. For supratentorial/hemispheric HGG, maximal surgical resection is followed by radiotherapy (for patients older than age 4 years) and concomitant/adjuvant chemotherapy. On the basis of positive adult data with temozolomide80 and its decreased toxicity compared with other regimens,81 radiochemotherapy with temozolomide is widely considered as the therapeutic backbone. However, evidence for efficacy of the latter is currently unclear.

Future clinical trials will need to recognize the diversity of these tumors as opposed to an all-comers approach. This will require upfront molecular characterization of tumor tissue, including for DIPGs. When performed in a safe, standardized setting, stereotactic biopsy of DIPGs allows identification of actionable alterations as part of molecularly informed studies (eg, Fontebasso et al53 and Worst et al82). Furthermore, increased efforts are required to ascertain tumor material at relapse (or at autopsy), which would give important information about disease progression. Although core drivers may be both spatially and temporally stable, additional modifying alterations in subpopulations can also play important roles (see Nikbakht et al83).

In contrast to MEKi for LGG, the heterogeneity of HGG means that any single drug is unlikely to work for a large proportion of patients. Molecularly informed trials will therefore require global collaboration to conduct adequately powered studies. Initiatives such as international DIPG registries will help improve characterization of these tumors and facilitate trial planning.84,85 Individual examples of bench-to-bedside translation also indicate that studying acquired resistance mechanisms will be another challenge.70 Expanding the repertoire of patient-derived preclinical models will help when testing epigenetic modifier therapies for HGG,86,87 some of which are now entering clinical trials ( identifier: NCT02717455).

Although hurdles such as drug delivery across the blood-brain barrier (especially in DIPGs) remain to be overcome, recent progress in understanding these tumors means that enthusiasm within the research community is greater than ever.

Here we have provided an overview of current concepts on diagnosis, biology, and clinical management for the extremely heterogeneous group of pediatric gliomas. For more detail on some of these aspects, we direct the reader to additional recent reviews, a selection of which is provided in Table 1. Although our knowledge of the biology of pediatric gliomas has expanded enormously in recent years, significant challenges remain in translating these insights into clinical practice. For example, the true intertumoral heterogeneity of this group is far wider than anticipated and also broader than what is captured by current diagnostic practice. Definition of combined histo-molecular subgroups of glioma for prognostication and stratification onto (targeted) treatment trials will therefore be of key importance—something which hopefully will be addressed through initiatives such as the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT) group.88 In particular, precise prognostic markers and subgroups for BRAF V600E–mutated tumors would be of substantial value, because tumors with this readily druggable target show a spectrum of low- and high-grade histologies and a varied clinical course.


Table 1. Selected Recent Review Articles Summarizing Our Current Understanding of Pediatric Gliomas (see also references therein)

Thus, informative clinical trials in pediatric glioma will require comprehensive molecular characterization at diagnosis to enable precision therapy. The optimal time point for targeted therapies in patients with LGGs needs to be determined, and ranges from adjuvant therapy, even for completely resected tumors, to approaches restricted to relapsed or refractory disease. In HGGs, the delineation of distinct risk groups based on DNA methylation or gene sequencing data could be a next step toward an improved interpretation of clinical trial data. International multicenter trials will be the only way to address these issues rapidly, given the rarity of distinct subgroups.

More detailed characterization of the oncogenic effects of alterations such as histone and ATRX mutations in HGG or MYB in LGG will also be essential for providing additional insight and possible therapeutic vulnerabilities. The importance of understanding signaling networks and feedback loops within the MAPK pathway, for example, is seen from the paradoxical activation by first-generation RAF inhibitors. Such data may also help identify mechanisms of treatment resistance and suggest rational combinations to overcome them.

The availability of good preclinical in vitro and in vivo models, particularly for LGG, is another translational bottleneck. The development of such models will enable more functional studies such as high-throughput genetic or compound screening for novel drug targets. In addition, these models need to be used in a more sophisticated way when planning preclinical studies to improve their predictive value (eg, comparison with standard-of-care therapy and use of multiple models to better mimic clinical trials).

There is much work still to be done, but recent advances in LGGs and HGGs provide a framework for the road ahead. For some entities, that road is relatively clear (eg, second-generation RAF inhibitors with or without MEKi for V600E-mutant tumors), whereas for others, the path will likely have more twists and turns (eg, K27-mutant DIPGs). Overall, however, our improved understanding provides grounds for optimism that meaningful clinical benefit can be achieved in the not-too-distant future.

© 2017 by American Society of Clinical Oncology

Conception and design: All authors

Financial support: Stefan M. Pfister

Collection and assembly of data: Dominik Sturm, David T.W. Jones

Data analysis and interpretation: Dominik Sturm, David T.W. Jones

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

Pediatric Gliomas: Current Concepts on Diagnosis, Biology, and Clinical Management

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to or

Dominik Sturm

Patents, Royalties, Other Intellectual Property: PCT/CA2012/050834 Mutations of histone proteins associated with proliferative disorders

Stefan M. Pfister

Patents, Royalties, Other Intellectual Property: PCT/CA2012/050834 Mutations of histone proteins associated with proliferative disorders

David T.W. Jones

Patents, Royalties, Other Intellectual Property: PCT/CA2012/050834 Mutations of histone proteins associated with proliferative disorders

1. Ostrom QT, Gittleman H, Xu J, et al: CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009-2013. Neuro Oncol 18:v1-v75, 2016 Crossref, MedlineGoogle Scholar
2. Louis DN, Ohgaki H, Wiestler OD, et al (eds): WHO Classification of Tumours of the Central Nervous System, (ed 4) Revised. Lyon, France, IARC, 2016 Google Scholar
3. Huse JT, Snuderl M, Jones DT, et al: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): An epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol 133:417-429, 2017 Google Scholar
4. Stokland T, Liu JF, Ironside JW, et al: A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: A population-based cohort study (CCLG CNS9702). Neuro Oncol 12:1257-1268, 2010 MedlineGoogle Scholar
5. Armstrong GT, Conklin HM, Huang S, et al: Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol 13:223-234, 2011 Crossref, MedlineGoogle Scholar
6. Mistry M, Zhukova N, Merico D, et al: BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 33:1015-1022, 2015 LinkGoogle Scholar
7. Northrup H, Krueger DA: Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:243-254, 2013 Crossref, MedlineGoogle Scholar
8. Lewis RA, Gerson LP, Axelson KA, et al: von Recklinghausen neurofibromatosis: II. Incidence of optic gliomata. Ophthalmology 91:929-935, 1984 Crossref, MedlineGoogle Scholar
9. Fryssira H, Leventopoulos G, Psoni S, et al: Tumor development in three patients with Noonan syndrome. Eur J Pediatr 167:1025-1031, 2008 Crossref, MedlineGoogle Scholar
10. Sanford RA, Bowman R, Tomita T, et al: A 16-year-old male with Noonan’s syndrome develops progressive scoliosis and deteriorating gait. Pediatr Neurosurg 30:47-52, 1999 Crossref, MedlineGoogle Scholar
11. Schuettpelz LG, McDonald S, Whitesell K, et al: Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer 53:1147-1149, 2009 Crossref, MedlineGoogle Scholar
12. Jones DT, Hutter B, Jäger N, et al: Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45:927-932, 2013 Crossref, MedlineGoogle Scholar
13. Zhang J, Wu G, Miller CP, et al: Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 45:602-612, 2013 Crossref, MedlineGoogle Scholar
14. Jones DT, Kocialkowski S, Liu L, et al: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673-8677, 2008 Crossref, MedlineGoogle Scholar
15. Jones DT, Kocialkowski S, Liu L, et al: Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28:2119-2123, 2009 Crossref, MedlineGoogle Scholar
16. Schindler G, Capper D, Meyer J, et al: Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397-405, 2011 Crossref, MedlineGoogle Scholar
17. Rodriguez FJ, Schniederjan MJ, Nicolaides T, et al: High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN). Acta Neuropathol 129:609-610, 2015 Crossref, MedlineGoogle Scholar
18. Qaddoumi I, Orisme W, Wen J, et al: Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 131:833-845, 2016 Crossref, MedlineGoogle Scholar
19. Raabe EH, Lim KS, Kim JM, et al: BRAF activation induces transformation and then senescence in human neural stem cells: A pilocytic astrocytoma model. Clin Cancer Res 17:3590-3599, 2011 Crossref, MedlineGoogle Scholar
20. Ramkissoon LA, Horowitz PM, Craig JM, et al: Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A 110:8188-8193, 2013 Crossref, MedlineGoogle Scholar
21. Tatevossian RG, Tang B, Dalton J, et al: MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathol 120:731-743, 2010 Crossref, MedlineGoogle Scholar
22. Rivera B, Gayden T, Carrot-Zhang J, et al: Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol 131:847-863, 2016 Crossref, MedlineGoogle Scholar
23. Jacob K, Quang-Khuong DA, Jones DT, et al: Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17:4650-4660, 2011 Crossref, MedlineGoogle Scholar
24. Bandopadhayay P, Ramkissoon LA, Jain P, et al: MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48:273-282, 2016 Crossref, MedlineGoogle Scholar
25. Ater JL, Zhou T, Holmes E, et al: Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: A report from the Children’s Oncology Group. J Clin Oncol 30:2641-2647, 2012 LinkGoogle Scholar
26. Bouffet E, Scheinemann K, Zelcer SM, et al: Weekly vinblastine in chemotherapy-naive children with unresectable or progressive low grade glioma: A Canadian cooperative study. J Clin Oncol 31, 2013 (suppl; abstr 10029) Google Scholar
27. Gnekow AK, Falkenstein F, von Hornstein S, et al: Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol 14:1265-1284, 2012 Crossref, MedlineGoogle Scholar
28. Nicholson HS, Kretschmar CS, Krailo M, et al: Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: A report from the Children’s Oncology Group. Cancer 110:1542-1550, 2007 Crossref, MedlineGoogle Scholar
29. Packer RJ, Pfister S, Bouffet E, et al: Pediatric low-grade gliomas: Implications of the biologic era. Neuro Oncol 19:750-761, 2017 Google Scholar
30. Franz DN, Belousova E, Sparagana S, et al: Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381:125-132, 2013 Crossref, MedlineGoogle Scholar
31. Dombi E, Baldwin A, Marcus LJ, et al: Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med 375:2550-2560, 2016 Crossref, MedlineGoogle Scholar
32. Kieran M, Bouffet E, Tabori U, et al: The first study of dabrafenib in pediatric patients with BRAF V600-mutant relpased or refractory low-grade gliomas. Presented at the Annual Meeting of the European Society For Medical Oncology, Copenhagen, Denmark, Oct 7-11, 2016 Google Scholar
33. Karajannis MA, Legault G, Fisher MJ, et al: Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol 16:1408-1416, 2014 Crossref, MedlineGoogle Scholar
34. Sievert AJ, Lang SS, Boucher KL, et al: Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci U S A 110:5957-5962, 2013 Crossref, MedlineGoogle Scholar
35. Sun Y, Alberta JA, Pilarz C, et al: A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol 19:774-785, 2017 Google Scholar
36. Broniscer A, Chamdine O, Hwang S, et al: Gliomatosis cerebri in children shares molecular characteristics with other pediatric gliomas. Acta Neuropathol 131:299-307, 2016 Crossref, MedlineGoogle Scholar
37. Buczkowicz P, Bartels U, Bouffet E, et al: Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: Diagnostic and therapeutic implications. Acta Neuropathol 128:573-581, 2014 Crossref, MedlineGoogle Scholar
38. Ceccarelli M, Barthel FP, Malta TM, et al: Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164:550-563, 2016 Crossref, MedlineGoogle Scholar
39. Sturm D, Orr BA, Toprak UH, et al: New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060-1072, 2016 Crossref, MedlineGoogle Scholar
40. Bax DA, Mackay A, Little SE, et al: A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res 16:3368-3377, 2010 Crossref, MedlineGoogle Scholar
41. Faury D, Nantel A, Dunn SE, et al: Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol 25:1196-1208, 2007 LinkGoogle Scholar
42. Paugh BS, Qu C, Jones C, et al: Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28:3061-3068, 2010 LinkGoogle Scholar
43. Paugh BS, Broniscer A, Qu C, et al: Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 29:3999-4006, 2011 LinkGoogle Scholar
44. Puget S, Philippe C, Bax DA, et al: Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 7:e30313, 2012 Crossref, MedlineGoogle Scholar
45. Zarghooni M, Bartels U, Lee E, et al: Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28:1337-1344, 2010 LinkGoogle Scholar
46. Schwartzentruber J, Korshunov A, Liu XY, et al: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226-231, 2012 Crossref, MedlineGoogle Scholar
47. Wu G, Broniscer A, McEachron TA, et al: Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251-253, 2012 Crossref, MedlineGoogle Scholar
48. Lewis PW, Müller MM, Koletsky MS, et al: Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340:857-861, 2013 Crossref, MedlineGoogle Scholar
49. Sturm D, Witt H, Hovestadt V, et al: Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425-437, 2012 Crossref, MedlineGoogle Scholar
50. Bender S, Tang Y, Lindroth AM, et al: Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24:660-672, 2013 Crossref, MedlineGoogle Scholar
51. Bjerke L, Mackay A, Nandhabalan M, et al: Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discov 3:512-519, 2013 Crossref, MedlineGoogle Scholar
52. Wu G, Diaz AK, Paugh BS, et al: The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444-450, 2014 Crossref, MedlineGoogle Scholar
53. Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, et al: Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46:462-466, 2014 Crossref, MedlineGoogle Scholar
54. Buczkowicz P, Hoeman C, Rakopoulos P, et al: Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46:451-456, 2014 Crossref, MedlineGoogle Scholar
55. Taylor KR, Mackay A, Truffaux N, et al: Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46:457-461, 2014 Crossref, MedlineGoogle Scholar
56. Korshunov A, Capper D, Reuss D, et al: Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. Acta Neuropathol 131:137-146, 2016 Crossref, MedlineGoogle Scholar
57. Gielen GH, Gessi M, Hammes J, et al: H3F3A K27M mutation in pediatric CNS tumors: A marker for diffuse high-grade astrocytomas. Am J Clin Pathol 139:345-349, 2013 Crossref, MedlineGoogle Scholar
58. Gessi M, Gielen GH, Hammes J, et al: H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: Possible diagnostic and therapeutic implications? J Neurooncol 112:67-72, 2013 Crossref, MedlineGoogle Scholar
59. Solomon DA, Wood MD, Tihan T, et al: Diffuse midline gliomas with histone H3-K27M mutation: A series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 26:569-580, 2016 Crossref, MedlineGoogle Scholar
60. Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al: K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124:439-447, 2012 Crossref, MedlineGoogle Scholar
61. Castel D, Philippe C, Calmon R, et al: Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130:815-827, 2015 Crossref, MedlineGoogle Scholar
62. Aboian MS, Solomon DA, Felton E, et al: Imaging characteristics of pediatric diffuse midline gliomas with histone H3 K27M mutation. AJNR Am J Neuroradiol 38:795-800, 2017 Crossref, MedlineGoogle Scholar
63. Gessi M, Gielen GH, Dreschmann V, et al: High frequency of H3F3A (K27M) mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. Acta Neuropathol 130:435-437, 2015 Crossref, MedlineGoogle Scholar
64. Sturm D, Bender S, Jones DT, et al: Paediatric and adult glioblastoma: Multiform (epi)genomic culprits emerge. Nat Rev Cancer 14:92-107, 2014 Crossref, MedlineGoogle Scholar
65. Paugh BS, Zhu X, Qu C, et al: Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res 73:6219-6229, 2013 Crossref, MedlineGoogle Scholar
66. Bechet D, Gielen GG, Korshunov A, et al: Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol 128:733-741, 2014 Crossref, MedlineGoogle Scholar
67. Gessi M, Capper D, Sahm F, et al: Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol 132:635-637, 2016 Crossref, MedlineGoogle Scholar
68. Pagès M, Beccaria K, Boddaert N, et al: Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma. Brain Pathol doi:10.1111/bpa.12473 [epub ahead of print on December 16, 2016] Google Scholar
69. Korshunov A, Schrimpf D, Ryzhova M, et al: H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathol doi:10.1007/s00401-017-1710-1 [epub ahead of print on April 11, 2017 Google Scholar
70. Bender S, Gronych J, Warnatz HJ, et al: Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat Med 22:1314-1320, 2016 Crossref, MedlineGoogle Scholar
71. Korshunov A, Ryzhova M, Hovestadt V, et al: Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669-678, 2015 Crossref, MedlineGoogle Scholar
72. Huillard E, Hashizume R, Phillips JJ, et al: Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc Natl Acad Sci U S A 109:8710-8715, 2012 Crossref, MedlineGoogle Scholar
73. Bautista F, Paci A, Minard-Colin V, et al: Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatr Blood Cancer 61:1101-1103, 2014 Crossref, MedlineGoogle Scholar
74. Robinson GW, Orr BA, Gajjar A: Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer 14:258, 2014 Crossref, MedlineGoogle Scholar
75. Broniscer A, Tatevossian RG, Sabin ND, et al: Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma. Neuropathol Appl Neurobiol 40:327-336, 2014 Crossref, MedlineGoogle Scholar
76. Kleinschmidt-DeMasters BK, Aisner DL, Birks DK, et al: Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol 37:685-698, 2013 Crossref, MedlineGoogle Scholar
77. Bouffet E, Larouche V, Campbell BB, et al: Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 34:2206-2211, 2016 LinkGoogle Scholar
78. Hargrave D, Bartels U, Bouffet E: Diffuse brainstem glioma in children: Critical review of clinical trials. Lancet Oncol 7:241-248, 2006 Crossref, MedlineGoogle Scholar
79. Jansen MH, van Vuurden DG, Vandertop WP, et al: Diffuse intrinsic pontine gliomas: A systematic update on clinical trials and biology. Cancer Treat Rev 38:27-35, 2012 Crossref, MedlineGoogle Scholar
80. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 Crossref, MedlineGoogle Scholar
81. Cohen KJ, Pollack IF, Zhou T, et al: Temozolomide in the treatment of high-grade gliomas in children: A report from the Children’s Oncology Group. Neuro Oncol 13:317-323, 2011 Crossref, MedlineGoogle Scholar
82. Worst BC, van Tilburg CM, Balasubramanian GP, et al: Next-generation personalised medicine for high-risk paediatric cancer patients: The INFORM pilot study. Eur J Cancer 65:91-101, 2016 Crossref, MedlineGoogle Scholar
83. Nikbakht H, Panditharatna E, Mikael LG, et al: Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nat Commun 7:11185, 2016 Crossref, MedlineGoogle Scholar
84. Baugh J, Bartels U, Leach J, et al: The international diffuse intrinsic pontine glioma registry: An infrastructure to accelerate collaborative research for an orphan disease. J Neurooncol 132:323-331, 2017 Crossref, MedlineGoogle Scholar
85. Veldhuijzen van Zanten SE, Baugh J, Chaney B, et al: Development of the SIOPE DIPG network, registry and imaging repository: A collaborative effort to optimize research into a rare and lethal disease. J Neurooncol 132:255-266, 2017 Crossref, MedlineGoogle Scholar
86. Grasso CS, Tang Y, Truffaux N, et al: Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 21:827, 2015 Crossref, MedlineGoogle Scholar
87. Hashizume R, Andor N, Ihara Y, et al: Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 20:1394-1396, 2014 Crossref, MedlineGoogle Scholar
88. Louis DN, Aldape K, Brat DJ, et al: Announcing cIMPACT-NOW: The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. Acta Neuropathol 133:1-3, 2017 Crossref, MedlineGoogle Scholar


No companion articles


DOI: 10.1200/JCO.2017.73.0242 Journal of Clinical Oncology 35, no. 21 (July 20, 2017) 2370-2377.

Published online June 22, 2017.

PMID: 28640698

ASCO Career Center