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. [email protected]
& Pratiti [email protected]
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
123
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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