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This article is protected by copyright. All rights reserved.

BRAF V600E expression and distribution in desmoplastic infantile astrocytoma

/ ganglioglioma1

Christian Koelsche1,2, Felix Sahm1,2, Werner Paulus3, Michel Mittelbronn4, Felice

Giangaspero5, Manila Antonelli5, Jochen Meyer2, Felix Lasitschka6, Andreas von

Deimling1,2 and David Reuss1,2

1Department of Neuropathology, Ruprecht-Karls-Universitt Heidelberg, Heidelberg, Germany

2Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg,

Germany

3Institute of Neuropathology, University Hospital Mnster, Mnster, Germany

4Institute of Neurology (Edinger Institute), University of Frankfurt, Frankfurt, Germany

5Department of Radiological Oncological Sciences and Pathology, Universit Sapienza, Roma, Italy

6Institute of Pathology, Ruprecht-Karls-Universitt Heidelberg, Heidelberg, Germany

Corresponding Author

David Reuss, MD

Ruprecht-Karls-Universitt Heidelberg

Department of Neuropathology

Im Neuenheimer Feld 224

D-69120 Heidelberg

Fon: +49 (0)6221 56 4651

Fax: +49 (0)6221 56 4566

Email: [email protected]

Running title: BRAF V600E mutation in DIA/DIG

This article has been accepted for publication and undergone full peer review but has not been through the

copyediting, typesetting, pagination and proofreading process, which may lead to differences between this

version and the Version of Record. Please cite this article as doi: 10.1111/nan.12072

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Key words: desmoplastic infantile astrocytoma, desmoplastic infantile ganglioglioma, BRAF,

BRAF V600E, glioma, tumour, VE1, immunohistochemistry

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Abstract

Aims: Desmoplastic infantile astrocytoma / ganglioglioma (DIA/DIG) is a rare primary

neuroepithelial brain tumour typically affecting paediatric patients younger than 24

months. Knowledge about genetic alterations in DIA/DIG is limited. However, a

previous study on BRAF V600E mutation in paediatric glioma revealed a BRAF

mutation in one of two tested DIAs/DIGs. The limited number of cases in that study

did not allow any conclusion about mutation frequency ofBRAFin this tumour entity.

Methods: We collected a series of 18 DIAs/DIGs for testing BRAFV600E mutational

status by BRAF V600E immunohistochemistry (clone VE1). Cases with sufficient

DNA were tested forBRAFV600E mutation by pyrosequencing.

Results: Three out of 18 DIAs/DIGs presented with VE1 binding. A considerable

proportion ofBRAFV600E mutated tumour cells was detected in the cortical tumour

component, whereas the pronounced leptomeningeal tumoral stroma was

predominantly negative for VE1 binding. Pyrosequencing confirmed BRAF V600E

mutation in two of three VE1 positive cases.

Conclusion: BRAF V600E mutation affects a subset of DIAs/DIGs and offers new

therapeutic opportunities.

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Introduction

Desmoplastic infantile astrocytoma / ganglioglioma (DIA/DIG) is a meningocerebral

neuroepithelial tumour with a pronounced desmoplastic leptomeningeal tumour

component [1]. The overall incidence of DIAs/DIGs has been estimated at less than

0.3 %, but when limited to infancy age, DIAs/DIGs accounts for approximately 16 %

of intracranial tumours [2, 3]. Most DIAs/DIGs have been described in paediatric

patients younger than 24 months. However, rare cases have been reported in

paediatric patients exceeding this age-range [4]. DIAs/DIGs almost always grow

supratentorial favouring the fronto-temporal region [4]. Upon neuroimaging

DIAs/DIGs typically present with a cystic mass of deep localization and a peripheral

solid tumour portion [5].

Histologically, the neuroepithelial tumour can present with purely astrocytic

differentiation (DIA) or be composed of tumour cells with astrocytic and neuronal

differentiation (DIG) [1]. Due to their very close histomorphological relationship, DIAs

and DIGs have been categorized together in the WHO classification of tumours of the

central nervous system [1]. DIA/DIG corresponds to WHO grade I because of their

benign biological behaviuor with a favorable clinical course even after subtotal

resection, [1, 2, 6]. Nevertheless, single cases have been reported with signs of

malignant transformation or multifocal intracranial growth which then behaved

aggressively [7, 8].

Knowledge of the genetic background in DIA/DIG is very limited and cytogenetic data

are only available of a small number of cases. TP53 mutation, which is often found in

diffuse astrocytoma, was not found in DIA/DIG and suggests no close genetic

relation of these entities [9]. Furthermore, an array CGH based study of 3 DIAs/DIGs

revealed no consistent chromosomal gains or losses [10].

Recently, point mutation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF)

at codon position 600 has been shown in roughly 60 % of ganglioglioma and 10 % of

pilocytic astrocytoma [11-13]. Due to their close relation regarding clinical

presentation and histological features, a similar genetic background has been

assumed [14]. Data about BRAFV600E mutation in DIA/DIG are very limited. One

sequencing-based study revealed BRAFV600E mutation in a single DIG case [15].

However, the small number of investigated DIGs did not allow any extrapolation in

terms of incidence ofBRAFV600E mutation.

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The present study was conducted to investigate the frequency of BRAF V600E

mutation in 18 DIAs/DIGs by applying the BRAFV600E mutation specific monoclonal

antibody clone VE1.

Materials and methods

Tissue samples and patient characteristics and histology

In total, 16 DIGs and 2 DIAs WHO grade I were included in this study. Tissue

samples were retrieved from the archives of the Department of Neuropathology of

the University Heidelberg, of the Department of Neuropathology of the University

Bonn, of the Department of Radiological Oncological Sciences and Pathology of the

University of Roma (Italy), of the Institute for Neuropathology of the University

Mnster, of the Institute of Neurology (Edinger-Institute) Frankfurt. The median age

at surgery was 10.5 months (ranging from 1 to 60 months) and the female/male

gender ratio was 0.8. Tumour growth was located supratentorial for 17 cases and in

the posterior fossa for one case. All cases with available neuroimaging report

presented with a large cystic neocortical lesion (Table 1). All included DIAs/DIGs

were reviewed by members of the Department of Neuropathology Heidelberg (CK,

FS, DR) and diagnosed according to the revised WHO 2007 classification of brain

tumours [1]. The study was performed in accordance with the guidelines of the

ethical policies of the involved institutions.

IHC, assessment and microscopy

To ensure proper antigenicity for IHC we used fresh-cut slides from formalin-fixed

paraffin embedded tissue which was not previously frozen and was free of

coagulation artifacts. Sections cut to 4 m were dried at 80C for 15 min and stained

with BRAF V600E specific clone VE1 on a Ventana BenchMark XT immuno stainer

(Ventana Medical Systems, Tucson, USA). The Ventana staining procedure included

pretreatment with cell conditioner 1 (pH 8) for 64 min, followed by incubation with

VE1 hybridoma supernatant (monoclonal, dilution 1:5) at 37C for 32 min. Antibody

incubation was followed by OptiView HQ Universal Linker for 12 min, incubation with

OptiView HRP Multimer for 12 minutes, signal amplification including the Ventana

OptiView Amplification Kit (Ventana, catalogue number 760-099), counterstaining

with one drop of haematoxylin for 4 min and one drop of bluing reagent for 4 min. As

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positive and negative controls a tissue micro array consisting of 4 melanoma

samples with known BRAF V600 status (2 BRAFwild type, 2 BRAFV600E) were

included in every staining run. VE1 was scored as either positive or negative.

Macro-, Laser-capture microdissection and DNA extraction

Macro-dissection was performed of corresponding VE1 positive areas on unstained

slides of 10 m thickness and collected in 1.5 ml Eppendorf Safe-Lock tubes

(Eppendorf AG). For LASER-assisted microdissection VE1 stained slides of 10 m

thickness were washed in ethanol and incubated for 5 min in xylene. After air-drying

the slides were dissected by the Microbeam LMPC System (Carl Zeiss

MicroImaging) using the RoboLPC method. Dissected material was captured and

collected in 1.5 ml AdhesiveCaps opaque (Carl Zeiss MicroImaging). DNA was

extracted applying the NucleoSpin Tissue XS kit (Machery-Nagel) according to the

manufacturers instructions.

Sequencing

DNA was available from 4 DIGs and 1 DIA. Pyrosequencing for codon 600 of BRAF

was performed as previously described [16]. The sequence was compared with

GenBank sequence NM_004333 forBRAFas reference.

Results

A total of 16 DIGs and two DIAs were screened for BRAF V600E mutated protein by

applying VE1 IHC (Table 1). Three cases, two DIGs and one DIA, presented with

VE1 immunoreactivity (Figure 1).

Expression and distribution of BRAF V600E mutated protein in DIA/DIG

A case of an 6 month old infant with a cystic lesion localized in the temporal lobe (ID

60212) was diagnosed as DIG and exhibited the predominant BRAF V600E positive

tumour cell proportion in the cortical tumour component, which presented as a

subpial ribbon of cells (Figure 1a,b). BRAF V600E positive tumour cells were also

found accentuated around cortical vessels (Figure 1c). In this region, space-

occupying subpial cystic changes and distinctive regions with a spongy, microcystic

appearance were apparent. Both the ganglionic and the undifferentiated

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neuroepithelial tumour cell component were positive for synapthophysin and VE1.

The desmoplastic leptomenigeal component contributed the largest tumour part and

presented with small nests of BRAF V600E expressing tumour cells. VE1 negative

spindle cells surrounded these nests. Nevertheless, even if most cortical tumour cells

were VE1 positive, they made only the minor tumour cell fraction in the desmoplastic

leptomeningeal tumour region (Figure 1c).

The second VE1 positive DIG (ID 60192) developed in the occipital lobe of a 5 year

old child. The tissue solely comprised of the desmoplastic leptomeningeal tumour

component. Here, small nests of tumour cells faintly bound VE1 (Figure 1d,e).

The BRAFV600E mutated DIA (ID 56972) occurred in the suprasellar region of a 4

months young infant. The tumour bulk completely consisted of desmoplastic tumour

tissue with VE1 positive tumour cells arranged in nests surrounded by predominantly

VE1 negative spindle-shaped cells (Figure S1).

Confirmation ofBRAFV600E mutation by DNA-based method

VE1 specificity was verified by pyrosequencing ofBRAFcodon 600 in 5 cases (Table

1). All VE1 negative cases with DNA available were confirmed as BRAF wt.

Pyrosequencing revealed BRAFV600E mutation in case 57094 and 60212. For the

latter one macro-dissection of VE1 positive cells was performed to enrich tumour

DNA. The cortical and desmoplastic leptomeningeal tumour components were

separately dissected. BRAF V600E mutated allele was detected in both fractions,

however the allelic frequency ofBRAFV600E mutation was somewhat lower in the

desmoplastic region (Figure 1b,c inlet).

The small amount of VE1 positive cells in case 60192 impeded the confirmation of

BRAF mutation by sequencing. Preceding laser-capture microdissection was

performed to enrich the proportion of VE1 positive tumour cell DNA. However, BRAF

V600E mutant alleles were not detected.

Discussion

BRAF mutation has been shown to play a pivotal role in glioma tumorigenesis,

especially in paediatric patients [12, 15, 17]. The close relationship of DIA/DIG with

pilocytic astrocytoma and ganglioglioma, the latter harboring BRAFV600E mutation

in the majority of cases, and the previously described detection of BRAF V600E

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mutation in a single DIG case raised the hypothesis that BRAFmutation might also

be a common genetic alteration contributing to DIA/DIG tumorigenesis [12-14].

BRAF V600E (VE1) binding was detected in 3 of 18 DIA/DIG and confirmation by

sequencing was yielded in two cases (IDs 57094 and 60212). VE1 binding was

confined to the non-spindle cell component whereas the desmoplastic spindle-

shaped cells were predominantly VE1 negative. Of note, almost all DIAs/DIGs

reported here presented with a pronounced leptomeningeal desmoplastic tumour

component, whereas the cortical component was lacking or represented a minor

fraction of samples. Since spindle-shaped cells in the leptomeningeal component

were predominantly VE1 negative, tumour cell dilution by these VE1 negative cells

possibly reduced the probability of finding mutation by DNA-based methods and

might explain the failure ofBRAFV600E confirmation by sequencing for case 60192.

However, BRAF V600E mutation specific antibody staining is a useful tool in

particular for tumour regions with low tumour-cell density resulting from prominent

desmoplasia, for instance. VE1 IHC allows the detection of BRAF V600E mutated

protein close to the single cell level. Previous studies have confirmed the high

reliability, sensitivity and feasibility of BRAF V600E (VE1) antibody application in

such tumour entities [12, 18-23].

Furthermore, VE1 IHC has the advantage of being able to evaluate the distribution of

BRAF V600E mutated protein in tissue. Case 60212 was suitable for a

comprehensive examination of the expression and distribution of BRAF V600E

mutated protein in both the cortical and leptomeningeal tumour component.

Interestingly, the cortical tumour region presented with a prominent subpial ribbon

and angiocentric pattern of VE1 positive tumour cells, whereas the leptomeningeal

tumour part had intermingled groups of VE1 binding cells. Previous studies had

assumed that somatic mutations of common neoplastic precursor cells like

specialized subpial glial cells might lead to brain tumours with neocortical localization

and a close relation to the meninges [9]. The cortical ribbon of VE1 positive cells

might reflect the subpial origin of DIA/DIG.

Case 60192 solely covered a small part of the leptomeningeal desmoplastic tumour

component. Thus, this case was ineligible for a comprehensive analysis of tumour

cell distribution. Nevertheless, the VE1 positive cells arranged in nests and were

surrounded by VE1 negative spindle shaped cells, a similar pattern as seen in case

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60212 and 57094. The distribution of VE1 positive cells in these cases may argue for

the cortical tumour cells as the true neoplastic component whereas the prominent

desmoplastic component may be purely reactive in nature.

Recently, we revealed the expression of BRAF V600E mutated protein in the

ganglionic tumour cell component of ganglioglioma [12]. Corresponding to the finding

in ganglioglioma, we also found an overlap of synaptophysin- and BRAF V600E

(VE1) staining in DIG case ID 60212 (Fig. S2). VE1 positive ganglionic cells were

detected in both the cortical and the desmoplastic leptomenigeal tumour part.

Interestingly, the frequency of BRAFV600E mutation in DIAs/DIGs is considerably

lower than in ganglioglioma (60%) [12, 13]. This may point to a different cell of origin

in the neuronal lineage which has a different susceptibility to BRAFV600E -induced

tumor initiation. Further studies are required to reveal more details about the

molecular relation between DIA/DIG and ganglioglioma including DNA-methylome

analysis.

The low rate of BRAF V600E mutation in DIA/DIG argues for additional molecular

mechanisms that drive tumorigenesis. Candidate alterations include those who also

activate the MAPK signaling pathway like Neurofibromin 1 (NF1) gene mutation or

BRAF-fusion. There are indeed single case reports about neurofibromatosis type I

associated DIG [24]. BRAF-fusion has almost exclusively been restricted to pilocytic

astrocytoma [25]. Accordingly, we did not find BRAF-KIAA1549 fusion in two cases

(ID 57094, 60210) analyzed by FISH analysis (data not shown). Nevertheless, a very

recent whole-exome sequencing based study of different paediatric low-grad glioma

revealed a new gene fusion involving Fragile X related protein 1 (FXR1) and BRAFin

one investigated DIG case.

However, deregulation of BRAF activity by fusion or point mutation indicates the

importance of MAPK signaling pathway in the development of DIA/DIG.

A favorable clinical course of DIA/DIG after gross total resection has been reported

for the great majority of cases, but malignant transformation and multifocal growth

have been reported in some cases [7, 8]. The latter cases may benefit from a

systemic therapeutic approach. New drugs targeting the MAPK signaling pathway, by

selective inhibition of BRAF mutated protein for instance, offer new therapeutic

options with promising results in BRAFV600E mutated melanoma metastases and

glioma [26-28].

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Recently, a case with a prenatal diagnosis of DIG has been reported [29]. The young

age of patients with DIA/DIG has raised the question whether DIA/DIG formation

starts with the mutation of a progenitor cell conferring to a selective growth

advantage. Some DIA/DIG cases might be caused by congenital mutations. Thus,

further investigation of the temporal and spatial development of DIA/DIG might give

new insights in the biology of this rare disease.

In summary, we described the presence of BRAF V600E mutation in a subset of

DIA/DIG and assigned the major proportion of BRAF V600E expressing tumour cells

to the cortical tumour region.

Figure 1:

BRAF V600E (VE1) immunohistochemistry of case 60212 (a-c) and case 60192

(d,e). (a) Overview of a DIG with cortical and desmoplastic leptomeningeal tumour

parts. (b) Corresponding magnification of the cortical tumour region with BRAF

V600E positive ribbon-like staining pattern (arrow) and angiotropism of BRAF V600E

mutated tumour cells (two-headed arrow). The inlet shows the BRAF codon 600

pyrogramm of this region with a T to A substitution in 16 % of alleles. (c)

Corresponding leptomeningeal tumour part with nests of VE1 positive tumour cells

surrounded by VE1 negative spindle-shaped cells. The inlet shows the BRAFcodon

600 pyrogramm of this region with a T to A substitution in 10 % of alleles. (d) VE1

staining of a DIG with faint positive tumour cell nests surrounded by VE1 negative

desmoplastic stroma. (e) Corresponding magnification of VE1 positive cell nests.

Magnification: (a) 4-fold; (b,c,e) 200-fold; (d) 30-fold.

Table 1: Clinical, immunohistochemical and molecular data of DIAs/DIGs

IDDiagnosis

(WHO grade)

Age atsurgery(month)

Sex Location VE1 Seq

60194 DIG (I) 1 m temporal - NA

60196 DIG (I) 2 m supratentorial - NA60214 DIG (I) 3 f posterior fossa - NA

60206 DIG (I) 4 f temporal - ND

56972 DIA (I) 4 m suprasellar + V600E

60188 DIG (I) 6 f temporo-parietal - NA

60198 DIG (I) 6 m supratentorial - NA

60212 DIG (I) 6 f temporal + V600E

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60200 DIG (I) 7 m parietal - NA

60216 DIG (I) 8 m temporo-parietal - NA

60202 DIG (I) 8 m frontal - NA

60218 DIA (I) 9 f frontal - NA

60220 DIG (I) 9 m frontal - wt

60222 DIG (I) 10 m occipital - NA

60204 DIG (I) 12 f supratentorial - NA

60190 DIG (I) 12 f supratentorial - wt

60210 DIG (I) 17 f fronto-parietal - NA

60192 DIG (I) 60 m occipital + wt

ID ~ internal patient number; DIG ~ desmoplastic infantile ganglioglioma; DIA ~

desmoplastic infantile astrocytoma; m ~ male; f~ female; NA ~ not available; VE1 ~

antibody clone VE1; - ~ immunonegative; + ~ immunopositive; Seq ~ BRAFcodon

600 pyrosequencing status; V600E ~ BRAFV600E mutation; wt ~ BRAFwild type;

Figure S1:

Sagittal postgadolinium T1-weighted (a) and sagittal T2- (CISS) weighted (b) MR

images of a 4 month old child showing a large primarily supratentorial solid-cystic

tumour. (a) The solid component (white arrow) shows heterogeneous enhancement

following gadolinium injection. (b) T2 (CISS) weighted images visualize a large

anterior and small posterior cystic component (white arrows). Note the subdural

hygroma surrounding the anterior cystic tumour mass. (c) H&E staining shows an

astrocytic tumour with abundant desmoplasia. (d) BRAF V600E (VE1)

immunohistochemistry shows positive tumor cells embedded in a desmoplastic

matrix. Magnification: (c-d) 200-fold. (e) BRAFcodon 600 pyrogramm with a T to A

substitution in 20 % of alleles.

Figure S2:

(a) BRAF V600E (VE1) staining of tumour cells in the desmoplastic component of

DIG case 60212. (b) Corresponding region stained against Synaptophysin (Syn)

revealed a similar staining pattern compared to VE1 IHC. Magnification: 100-fold.

Acknowledgments

The authors thank Tanja Goeck and Jutta Scheuerer for excellent technical

assistance, Philipp Kickingereder for MRI examination and images, and Andrey

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Korshunov forBRAF-KIAA1549 FISH analysis. This work was in part funded by the

Deutsche Forschungsgemeinschaft, SFB 938/TP Z2 (F.L.).

Conflict of interest

AvD has applied for a patent on the diagnostic use of BRAF V600E mutant-specific

antibody VE1. All terms are being managed by the German Cancer Research Center

in accordance with its conflict of interest policies.

Authors contribution

CK histologic imaging, data analysis and manuscript preparation

FS data analysis

WP collection of cases, clinical data

MM collection of cases, clinical data

FG collection of cases, clinical data

MA collection of cases

JM molecular analysis

FL molecular analysis

AvD data analysis, manuscript preparation

DR project conception, data analysis and manuscript preparation

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