CLINICAL STUDY

Disseminated glioneuronal tumors occurring in childhood:treatment outcomes and BRAF alterations including V600Emutation

Andrew J. Dodgshun1,2 • Nadine SantaCruz3,4 • Jaeho Hwang3,4 •

Shakti H. Ramkissoon7,11,12 • Hayley Malkin3,4 • Guillaume Bergthold3,4 •

Peter Manley3,4 • Susan Chi3,4 • Duncan MacGregor5 • Liliana Goumnerova3,4,13,14 •

Michael Sullivan1,6 • Keith Ligon7,8,11,12,15 • Rameen Beroukhim4,7,8,10•

Betty Herrington9 • Mark W. Kieran3,4 • Jordan R. Hansford1,6 •

Pratiti Bandopadhayay3,4,8,10

Received: 8 October 2015 / Accepted: 10 March 2016 / Published online: 19 March 2016! Springer Science+Business Media New York 2016

Abstract Disseminated glioneuronal tumors of childhood

are rare. We present a retrospective IRB-approved review

of the clinical course and frequency of BRAF mutations indisseminated glioneuronal tumors at two institutions.

Defining features of our cohort include diffuse lep-

tomeningeal-spread, often with a discrete spinal cordnodule and oligodendroglioma-like histologic features.

Patients were identified through a pathology database

search of all cases with disseminated low-grade neoplasmswith an oligodendroglioma-like component. De-identified

clinical information was collected by chart review and all

imaging was reviewed. We retrieved the results of targeted

genomic analyses for alterations in BRAF. Ten patients

(aged 2–14 years) were identified from the Dana-Farber/Boston Children’s Hospital and the Royal Children’s

Hospital, Melbourne pathology databases. Nine patients

received chemotherapy. Eight patients are alive, althoughthree have had episodes of progressive disease. We iden-

tified genomic alterations affecting the MAPK pathway in

six patients. One patient had a germline RAF1 mutationand a clinical diagnosis of cardio-facio-cutaneous syn-

drome. BRAF duplications were identified in four and

BRAF V600E mutation was identified in one. These datasupport the presence of targetable genomic alterations in

this disease.Andrew J. Dodgshun, Nadine SantaCruz, Jordan R. Hansford, andPratiti Bandopadhayay have contributed equally to this work.

& Andrew J. Dodgshunajdodgshun@gmail.com

& Pratiti BandopadhayayPratiti_Bandopadhayay@dfci.harvard.edu

1 Children’s Cancer Centre, Royal Children’s Hospital, 50Flemington Road, Parkville, Melbourne, VIC 3052, Australia

2 Department of Paediatrics, University of Melbourne,Melbourne, VIC 3052, Australia

3 Dana-Farber/Boston Children’s Cancer and Blood DisordersCenter, 450 Longwood Ave, Boston 02115, USA

4 Harvard Medical School, Boston, MA, USA

5 Department of Pathology, Royal Children’s Hospital,Melbourne, VIC 3052, Australia

6 Murdoch Children’s Research Institute, Melbourne,VIC 3052, Australia

7 Department of Medical Oncology, Dana-Faber CancerInstitute, Boston 02115, USA

8 Broad Institute of MIT and Harvard, Cambridge, USA

9 Department of Pediatrics, University of Mississippi MedicalCenter, Jackson, MS, USA

10 Department of Cancer Biology, Dana-Farber Cancer Institute,Boston, MA, USA

11 Department of Pathology, Brigham and Women’s Hospital,Boston, MA, USA

12 Department of Pathology, Boston Children’s Hospital,Boston, MA, USA

13 Department of Neurosurgery, Boston Children’s Hospital,Boston, MA, USA

14 Department of Neurosurgery, Harvard Medical School,Boston, MA, USA

15 Department of Pathology, Harvard Medical School, Boston,MA, USA

123

J Neurooncol (2016) 128:293–302

DOI 10.1007/s11060-016-2109-x

Keywords Pediatric glioma ! Oligodendroglioma !Glioneuronal ! Leptomeningeal neoplasms ! Proto-oncogene proteins B-raf

Introduction

Disseminated glioneuronal tumors in childhood are rare.

There have been attempts to classify them as a distinctpathological entity. Rodriguez et al. describe the largest series

of this entity occurring in children, including 36 patients and

labeling the tumor as ‘‘Disseminated oligodendroglial-likeleptomeningeal tumor of childhood’’ [1]. Prior to this report,

there have been several case series and case reports published

onwhat is likely to be the same entity, variably describing it as‘‘Diffuse Leptomeningeal Glioneuronal Tumor’’ [2], ‘‘Su-

perficiallyDisseminatedGlioma inChildren’’ [3], or ‘‘Diffuse

leptomeningeal oligodendrogliomatosis’’ [4–6]. Thesetumors are characterized radiologically by leptomeningeal

enhancement on MRI, usually involving the spinal cord and

basal cisterns. There are often cystic T2 hyperintense lesionsthat do not enhance with contrast. Discrete intraparenchymal

lesions are often found in the spinal cord [1–4].Histologically,

the lesions are characterized by low tumor density and com-posed of cells with rounded oligodendroglial-like cells dis-

persed in a background of desmoplasia [1–4]. A recent case

series describes them as ‘‘disseminated oligodendroglial-likeleptomeningeal tumors’’ and demonstrates the immunohisto-

chemical features of these tumors, showing positivity with

MAP2, S-100 and OLIG2 [7].Recent advances in genetic sequencing and gene

expression profiling have led to a greater understanding of

the genetic alterations in pediatric low-grade gliomas [8–11]. Compared to adult gliomas, pediatric low-grade

lesions have a distinct clinical course [12] and distinct

genomic alterations [8], displaying low mutation rates withfew copy number alterations. Genetic alterations resulting

in upregulation of the MAPK/ERK pathway dominate the

genetic landscape of pediatric low-grade gliomas (PLGG)and low-grade glioneuronal tumors, being found in 82 % of

tumors [11] (Fig. 1). Alterations of BRAF are frequent in

PLGG. The most commonly identified alterations areBRAF duplication and BRAF V600E mutation.

The BRAF V600E mutation is well described in pedi-

atric ganglioglioma [13], pleomorphic xanthoastrocytoma[14] and other low-grade gliomas [15]. BRAF duplication is

most commonly seen in pediatric pilocytic astrocytoma

[16] with KIAA1549 being the most common fusion part-ner. Oligodendrogliomas are extremely rare in the pediatric

population, however BRAF alterations are described in

oligodendrogliomas [17]. Importantly, a number of smallmolecule inhibitors of both BRAF (to target the BRAF

V600E mutation) and targets downstream of BRAF, such as

MEK inhibitors (to target increased signaling resultantfrom BRAF duplications), have been developed and are

currently in early phase clinical trials for children (Clini-

caltrials.gov: NCT01677741, NCT01089101). Althoughresults of efficacy trials are not yet available, multiple case

reports and case series suggest that dramatic responses may

be possible in some pediatric brain tumors [18–20].Though most disseminated glioneuronal tumors in

childhood have been reported to follow a relatively indo-lent clinical course, a subset of lesions may behave

aggressively, despite low-grade histology [1]. Outcome

data on 24 patients from the largest series of this tumorshowed 9 deaths over a period of up to 21 years [1]. The

range of outcomes other than death, and the requirement

for multiple lines of therapy have not been well describedin the literature. The place of expectant management is also

not established.

1p loss has been frequently described with or without 19qco-deletion in this tumor [1–3, 5, 21, 22]. The genomic pro-

files of these tumors are yet to be well-characterized, although

a recent series demonstrates that BRAF-KIAA fusion iscommon in these tumors, in addition to deletions on chro-

mosomes 1p and 19q [23]. Many tumors in this series pos-

sessed both BRAF-KIAA fusion and deletions at 1p ± 19q.Given the frequency of BRAF alterations in other

pediatric low-grade CNS neoplasms and pediatric oligo-

dendroglial tumors, we performed targeted profiling ofBRAF in our cohort of patients to characterize whether

these tumors harbor potentially targetable alterations in the

gene. We present a retrospective IRB-approved review ofthe clinical course of children diagnosed with disseminated

glioneuronal tumors and report further evidence of BRAF-

KIAA fusion in these tumors. In addition, we include thefirst report of the presence of a BRAF V600E mutation in

children with this disease.

Methods

With IRB approval, we performed a review of children

with disseminated glioneuronal tumors at Dana-Farber/

Boston Children’s Hospital, Massachusetts, USA andRoyal Children’s Hospital Melbourne, Australia. Patients

with low-grade, disseminated lesions with oligodendroglial

features were identified by performing a search of pathol-ogy databases. De-identified radiological, pathological and

clinical data were collected. All profiling of the BRAF gene

were performed in CLIA or NATA certified laboratories.Targeted sequencing of exon 15 of BRAF was per-

formed using previously described methodology, which

allows for sequencing of genomic DNA extracted from

294 J Neurooncol (2016) 128:293–302

123

formalin-fixed, paraffin-embedded tumor tissue. Forpatients 1–6 (Dana-Farber Cancer Institute), allele-specific

PCR was performed with primers for exon 15. Pyrose-

quencing was performed using a Qiagen kit with primersfor codons 599 to 601. For patients 7–10 (Royal Children’s

Hospital), targeted mutation detection was performed using

an IVD Strip Assay manufactured by ViennaLab Diag-nostics GMBH.

For patients 1–6, BRAF duplications were identified by

FISH analysis. FISH was performed on 4-lm tissue sectionsusing the D7Z1 DNA Probe (chromosome 7 alpha satellite

DNA) (Abbott Molecular) at 7p11.1-q11.1, using Home-

brew probes that map to the 50 and 30 regions of BRAF at7q34. For patients 7–10, translocations were detected by

RT-PCR as described by Jones et al. [24], and fusion gene

identity was confirmed by direct Sanger sequencing.

Results

We identified ten patients (6 males and 4 females) with

disseminated low-grade lesions with oligodendroglial fea-tures and radiologic features consistent with those

described in Rodriguez et al. (Table 1). Patients ranged inage from 19 months to 14 years (mean 7.3 years) at the

time of diagnosis. Presenting symptoms were varied, lar-

gely dependent on the site of tumor bulk (Table 1). Ninepatients had MRI imaging consistent with diffuse lep-

tomeningeal disease at diagnosis (Fig. 2). The final patient

(Patient 3, Table 1) initially presented with an isolatedtemporal lesion that later disseminated. Six patients had an

identifiable primary lesion, of which four were located in

the spinal cord. Table 1 shows the sites of primary tumorsin each patient.

Patient 10 (Table 1) had a background of cardio-facio-

cutaneous syndrome—a Noonan’s-like syndrome charac-terized by particular facial features, cardiac defects and

hyperkeratotic skin, in addition to growth and neurological

problems. This condition is classified among the ‘‘RAS-opathies’’, usually caused by activating mutations in BRAF

or MEK genes, and is known to predispose to cancers

including brain tumors [25, 26]. Our patient has charac-teristic facial and skin features as well as hypertrophic

cardiomyopathy, and harbors a germline RAF1 mutation.

All imaging was characterized by diffuse lep-tomeningeal enhancement, with scattered, T2 hyperintense,

Fig. 1 Schematic of the RAS/MAPK/ERK pathway with actionable targets indicated. Receptor tyrosine kinases indicated by ‘‘RTK’’. Examplesinclude PDGRF, FGFR and EGFR

J Neurooncol (2016) 128:293–302 295

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Tab

le1

Dem

ographic,radiological,pathological,treatm

entandmolecularinform

ation

Patient

number

Ageat

diagnosis

Sex

Primary

lesion

Presenting

symptoms

Pathologic

diagnosis

Treatment

Patient

outcome

Followup

(months)

BRAF

dup.

BRAF

V600E

13years

6months

MThalam

us

Neckpain,

headache

Biopsy

1—DNET

Vincristine/carboplatin

Off treatm

ent

stable

29

N/A

-

Biopsy

2—diffuse

glioneuronal

tumor

219months

MSpine

Headache,

vomiting

Biopsy

1—nondiagnostic

Vincristine/carboplatin

On treatm

ent

stable

46

?N/A

Biopsy

2—glioneuronal

lesion

Vinblastine

TPCV

37years

MTem

poral

lobe

Seizure

Glioneuronal

lesion

TPCV

Off treatm

ent

stable

19

N/A

?

43years

10months

MNone

Headache,

vomiting

Neuroectodermal

neoplasm

within

leptomeninges

Vincristine/carboplatinTPCV

Multiple

other

Diedof

disease

69

?N/A

511years

9months

FNone

Lower

limb

neuropathy

Disseminated

glioneuronal

lesion

Observation

Off treatm

ent

stable

16

N/A

N/A

614years

FSpine

Headache,

vomiting

Low

gradeneuroepithelial

tumor

Tem

ozolomideandradiation

Vincristine/carboplatin

TPCV

Diedof

disease

60

?N/A

73years

2months

MSpine

VInervepalsy

Biopsy

1and2—nondiagnostic

Cisplatin/Etoposide

Off treatm

ent

stable

29

?-

Biopsy

3—glioneuronal

lesion

Carboplatin

85years

4months

FSpine

Buttock

pain

DOLT

Vincristine/carboplatin?

bevacizumab

On treatm

ent

stable

17

N/A

N/A

914years

1months

FNone

Headache,

vomiting

DOLT

Vincristine/carboplatinSpinal

radiotherapy?

temozolomide/

irinotecan

On treatm

ent

stable

18

--

10

9years

1months

MNone

Scoliosis

Biopsy

1—nondiagnostic

Carboplatin

On treatm

ent

stable

6-

-

Biopsy

2—DOLT

DOLTdisseminated

oligodendroglial-likeleptomeningealtumor,N/A

nottested

296 J Neurooncol (2016) 128:293–302

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non-enhancing or heterogeneously enhancing nodular

lesions (Fig. 2). A biopsy was performed in all patients.Initial biopsy was inadequate in four patients who required

more than one biopsy to obtain diagnostic tissue. Final

histopathological diagnoses can be found in Table 1. In allcases, pathologic evaluation identified tumor cell with

oligodendroglial-like morphologies with a low-grade his-

tology. Tumor cells were diffusely GFAP positive andshowed heterogeneous expression for OLIG-2 and synap-

tophysin. Mitotic figures were rarely observed, and MIB1

proliferation indices ranged from 1 to 7 %. High-gradefeatures, including microvascular proliferation and necro-

sis, were not detected. Representative histology is shown in

Fig. 3.BRAF alteration testing (either V600E or 30BRAF

duplication) was performed in eight of the ten patients,

limited by insufficient tissue. We observed an alteration infive of the eight tumors tested (Fig. 4). BRAF duplication

was identified in four patients, and a BRAF V600E

mutation was identified in the fifth. BRAF V600E muta-

tions have not yet been reported in this disease. A sixthpatient was known to harbor a germline RAF1 mutation.

We did not observe a BRAF alteration in three tumors. Due

to the insufficient tissue, BRAF testing could not be per-formed in two patients. Acknowledging the limitation of

small numbers, there was no apparent difference in out-

come between those who had BRAF duplication, BRAFmutation or no detectable BRAF alteration.

Clinical outcome

Nine of ten patients received up-front treatment withchemotherapy or radiation and one has been followed by

observation only (Table 1; Fig. 4a). Five patients devel-

oped progressive disease (median time to progression7.6 months) and went on to receive additional

chemotherapy. Most patients received a carboplatin-

Fig. 2 Contrast enhanced spine MRI of patient 2 (a) demonstrates aprimary spinal nodule (arrowed). Contrast enhanced brain MRI ofpatient 2 (b) demonstrates diffuse leptomeningeal enhancement. T1

spinal images of patient 8 pre- (a) and post- (b) contrast showcircumferential involvement of the entire distal spinal cord withtumor resulting in flattening and displacement

J Neurooncol (2016) 128:293–302 297

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containing PLGG regimen at initial diagnosis. Other ther-

apies given at diagnosis included thioguanine/procar-

bazine/lomustine/vincristine (TPCV), cisplatin/etoposideand radiotherapy. Additional relapse therapies included

temozolomide ± irinotecan, everolimus and bevacizumab.

Two patients in our cohort (2/10, 20 %) died of theirdisease, and a third developed paraplegia. Patient 4

(Table 1) progressed 36 months from first treatment with

vincristine and carboplatin. Despite transient stability withTPCV and then bevacizumab, the tumor continued to

progress through everolimus, temozolomide and vin-

blastine, and the patient succumbed to his disease 6 yearsafter initial diagnosis. Patient 6 (Table 1) was initially

treated with craniospinal radiation and temozolomide. She

later progressed and was treated with vincristine and car-boplatin. She progressed a third time and was treated with

TPCV. This treatment was discontinued early due to pro-found myelosuppression. She later progressed and elected

not to pursue further tumor directed therapy and passed

away 5 years from diagnosis. Patient 9 (Table 1) startedtherapy with vincristine and carboplatin. She rapidly

deteriorated developing progressive bilateral leg weakness

and ultimately paraplegia by week 12 of treatment. Para-plegia was attributed to progressive spinal disease despite

apparent radiological stability, and at that point, her treat-

ment was changed to spinal radiotherapy with concurrenttemozolomide. Post radiation therapy, she completed

twelve courses of irinotecan and temozolomide. Her dis-

ease was radiologically stable after radiotherapy, but neu-rological function has markedly improved over 14 months

to the degree that she is able to walk with assistance.Eight of the ten patients are alive with a mean follow up

of 31 months. Neurologic sequelae include seizures

(n = 2), diabetes insipidus (n = 1), and paraplegia(n = 1). Three patients required the placement of VP

shunts to relieve hydrocephalus. Additional treatment

related complications include shunt failure (n = 3), shuntinfection (n = 1), and persistent vincristine related neu-

ropathy (n = 1).

We examined published cases series of children withdisseminated glioneuronal tumors to determine the clinical

outcomes of children diagnosed with disseminated

glioneuronal tumors (Table 2), and compared these out-comes to our cohort. There is a consistent subset of patients

(between 20 and 38 %) who suffer relentless progression

and death. A further subset have significant neurologicalsequelae, including cognitive dysfunction and paraplegia.

As neurological sequelae are not well reported, it may be

that our estimate of 10 % under-reports the morbidityassociated with this condition.

Discussion

We report the presence ofMAPK pathway alterations in sixof ten children with disseminated glioneuronal tumors,

including the first report of a BRAF V600E mutation and

the first report of this tumor in a child with a germlineRASopathy. These findings are consistent with a recent

paper highlighting BRAF duplications in a separate cohort

of patients [23]. Indeed alterations afflicting BRAF arepresent in more than 50 % of the patients across both

cohorts (Fig. 4b). The finding of BRAF alterations in these

tumors has clinical significance, as they represent poten-tially targetable genomic alterations. We also report clini-

cal outcomes, including one patient who received no

treatment and remained stable at 16 months, two deaths,and one patient with onset of paraplegia from tumor

progression.

Clinical outcomes in this entity are not well described. Itis known that up to a third of patients may die of this

tumor, but other outcomes are not well reported. The fac-

tors that determine clinical outcome remain elusive, high-lighting the need to develop targeted therapeutic strategies.

Fig. 3 The histologic appearances vary considerably within anindividual tumor. They include infiltration of thickened lep-tomeninges by bland cells with prominent perinuclear halos (a originalobjective 910), and other areas of diffuse growth of small glial cellswith bland nuclear morphology and sparse mitoses (b originalobjective 940)

298 J Neurooncol (2016) 128:293–302

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Radiology and pathology were similar for all of ourpatients and hence could not be relied upon to predict

outcome. Ultimately, tempo of disease as determined by

clinical symptoms drove treatment decisions for our cohort.The relative effectiveness of the various chemotherapy

regimens used cannot be commented upon, but the use of

PLGG regimens resulted in objective responses in somepatients and stability in others. One patient in our cohort

received spinal radiotherapy resulting in a dramaticreversal of neurological decline and ongoing improvement

more than 12 months after completion, suggesting relative

radiosensitivity in this disease.We present further evidence of BRAF-KIAA fusion in

disseminated glioneuronal lesions occurring in childhood

and the first report of a BRAF V600E mutation in childrenwith this disease, representing a potential therapeutic

Fig. 4 a Genomic alterations and clinical features of patients included in this study. b Incidence of BRAF alterations in DOLTs across twostudies (this report and those previously reported by Rodriguez et al. 2015 [23])

Table 2 Clinical outcomes reported in the literature

References Reported cases Deaths Neurological sequelaea Average length of followup (years)

Agamanolis et al. [3] 3 1 (33 %) 0 (0 %) 3

Gardiman et al. [2] 4 1 (25 %) 0 (0 %) 4

Preuss et al. [7] 4 1 (25 %) 1 (25 %) 4.5

Rodriguez et al. [1, 23] 24 9 (38 %) Not reported 5

Current report 10 2 (20 %) 1 (11 %) 2.5

Total 44 13 (30 %) 2 (10 %) 4

a Significant impairment of neurological or cognitive functioning

J Neurooncol (2016) 128:293–302 299

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target. Alterations in BRAF are being increasingly identi-

fied in pediatric brain tumors. Multiple BRAF inhibitorshave been developed and are in various stages of clinical

trials in pediatrics (Clinicaltrials.gov: NCT01748149,

NCT01677741). These inhibitors are particularly promis-ing for tumors that harbor the BRAF V600E mutation. In

contrast, the use of BRAF inhibitors in tumors that harbor

the BRAF duplication has been associated with paradoxicalactivating effect of the MAPK pathway and tumor growth

[27, 28].BRAF V600E mutations are found in a number of tumor

types, including melanoma and papillary thyroid carci-

noma, as well as pediatric CNS tumors. BRAF inhibitorssuch as vemurafenib have altered the landscape of meta-

static melanoma, a cancer with a high rate of BRAF V600E

mutation [29], resulting in 50 % response rates to singleagent therapy [30] and are currently in clinical trials for

children with BRAF V600E mutated tumors. More

recently, reports have highlighted dramatic responses tovemurafenib in children with BRAF V600E mutated CNS

tumors, including high-grade glioma and pleomorphic

xanthoastrocytoma [18–20].Although current BRAF inhibitors cannot be used to treat

tumors which harbor the BRAF duplication, other small

molecule inhibitors such as MEK inhibitors, or mTORinhibitors can be used to suppress MAPK activation down-

stream to the receptor. In addition, Type II BRAF inhibitors

suggest great preclinical promise for tumors that harborBRAF duplications. Phase I/II trials are currently underway

assessing the efficacy of the MEK inhibitor selumetinib

(Clinicaltrials.gov: NCT01089101, NCT01386450) in pedi-atric low-grade gliomas, specifically those harboring BRAF

duplications. Efficacy is currently unknown, but MEK

inhibition has been shown to be effective in other tumortypes harboring activating BRAF alterations [31]. mTOR

inhibitors, such as everolimus have an established place in

the treatment of sub-ependymal giant cell astrocytoma [32]and have shown promise in tumors such as PLGGs [33].

Our findings of BRAF alterations in disseminated

glioneuronal tumors demonstrate the importance of profil-ing the cancer genomes of rare tumors: to provide insights

into not only potential novel therapeutic targets, but also

the biology of rare tumors. Alterations in the MAPK/ERKpathway are frequent in PLGGs and are likely critical to

tumor development [8]. Other, described mutations in the

MAPK/ERK pathway in pediatric gliomas include alter-ations in FGFR2, NF1 and TS [11]. The finding of BRAF

alterations in some, but not all, disseminated glioneuronal

tumors leads to the question of whether alterations in othermembers of the MAPK/ERK pathway may be driver

mutations in BRAF wild-type tumors. This further supports

the need for comprehensive genomic profiling in pediatricdisseminated glioneuronal tumors. The discovery of a

disseminated glioneuronal tumor in a child with cardio-

facio-cutaneous with a germline RAF1 mutation lendsfurther evidence to the role this pathway plays in this

disease. This is consistent with reports of pilocytic astro-

cytoma, dysembryoblastic neuroepithelial tumor andjuvenile myelomonocytic leukemia in other ‘RASopathies’

such as Noonan and Costello syndrome [25].

There are several limitations to this study, particularlythat the sample size remains very small, a consequence of

the rarity of these tumors. We present results of targetedprofiling of BRAF alterations. However, we have not yet

comprehensively profiled the cancer genomes of these

tumors to determine the presence of other alterations thatmay be significant in tumorigenesis. This is of particular

significance for the three tumors in which we did not detect

BRAF alterations. Genome-wide sequencing of thesetumors will reveal the full landscape of these tumors and

may help better identify a subset of tumors associated with

a poor outcome.In summary, we add a further ten cases to the literature on

this rare and enigmatic entity. We describe a range of clinical

outcomes including one patient successfully observed withouttreatment and two patients who died of relentless progression.

We demonstrate the efficacy of chemotherapy and radio-

therapy for this entity and provide further rationale for the useof PLGG regimens for this related tumor. We also provide

further evidence of alterations of BRAF in children diagnosed

with disseminated glioneuronal tumors and report a BRAFV600E mutation for the first time as well as a child with

cardio-facio-cutaneous syndrome. This suggests that, like

many other pediatric low-grade gliomas, MAPK pathwayactivation is involved in the pathogenesis of these tumors.

These findings suggest the presence of an actionable alter-

ation in at least a subset of children with these disseminatedtumors. Further work is required to comprehensively profile

the genomic landscape of these rare tumors.

Acknowledgments We acknowledge the following funding sour-ces: A Kids’ Brain Tumor Cure Foundation Pediatric Low-GradeAstrocytoma Foundation (PB, KLL, RB, MWK, LG), Stop and ShopPediatric Brain Tumor Program (NSC, PB, MWK), St Baldrick’sFoundation (PB), Team Jack Foundation (PB, MWK, RB, LG),Andrysiak Fund for LGG (MWK), Jared Branfman Sunflowers ForLife Fund For Pediatric Brain And Spinal Cancer Research (PB, RB),Sontag Foundation (KLL, RB), Nuovo-Soldati Foundation (GB),Philippe Foundation (GB), Pediatric Brain Tumor Foundation (RB,PB), Royal Children’s Hospital Foundation (JH), Robert ConnorDawes Foundation (JH), Dr. Dodgshun is the recipient of the MurrayJackson Clinical Fellowship, Genesis Oncology Trust, New Zealand.

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