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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 5  |  Page : 168-174

BRAF mutation marks out specific subgroups of glioma


1 Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
2 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
3 Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China

Date of Web Publication25-Oct-2018

Correspondence Address:
Dr. Aden Ka-Yin Chan
Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_33_18

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  Abstract 

Background: Molecular markers including isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion have been incorporated into the World Health Organization (WHO) 2016 classification of diffuse gliomas for integrated diagnostic reporting. The prognostic relevance of BRAF mutation among the newly established molecularly defined entities of gliomas remained relatively unexplored. Materials and Methods: We examined BRAF mutation in 578 adult diffuse gliomas and examined the clinical significance of the mutation in five histomolecular subgroups, namely oligodendrogliomas, IDH-mutant and 1p/19q-codeleted (Group I), astrocytomas, IDH- mutant (Group II), astrocytomas, IDH-wild-type (Group III), glioblastoma, IDH-mutant (Group IV), and glioblastoma, IDH-wild type (Group V). Results: Mutation rate of BRAF was 5.9% across the whole cohort and was 4.9%, 7.5%, and 7.0% in Group II, Group III, and Group V gliomas, respectively. Univariate analysis revealed a trend of poor overall survival in BRAF-mutant tumors among Group II gliomas, a trend which was also demonstrated by multivariable analysis. Among Group III and Group V gliomas, BRAF-mutant tumors seemed to exhibit more favorable survival in univariate analysis. Multivariable analysis further demonstrated the favorable prognostic significance of BRAF mutation in Group III (hazard ratio [HR] = 0.31, 95% confidence interval [CI] = 0.10–0.95, P = 0.04) and Group V gliomas (HR = 0.44, 95% CI = 0.18–1.09, P = 0.077). Conclusion: BRAF mutation appears to mark out a small subset of adult infiltrative gliomas with the distinct clinical outcome. Mutational analysis of BRAF can potentially contribute to the clinical risk stratification in the management of glioma patients in the context of the WHO 2016 classification.

Keywords: BRAF mutation, clinical stratification, high-grade glioma, lower-grade glioma, prognostic biomarker


How to cite this article:
Chan AK, Zhang RR, Aibaidula A, Shi ZF, Chen H, Mao Y, Ng HK. BRAF mutation marks out specific subgroups of glioma. Glioma 2018;1:168-74

How to cite this URL:
Chan AK, Zhang RR, Aibaidula A, Shi ZF, Chen H, Mao Y, Ng HK. BRAF mutation marks out specific subgroups of glioma. Glioma [serial online] 2018 [cited 2022 Dec 7];1:168-74. Available from: http://www.jglioma.com/text.asp?2018/1/5/168/244191


  Introduction Top


The World Health Organization (WHO) classification of brain tumors has been undergoing revolutions with the incorporation of molecular markers into the classification system for integrated diagnostic reporting.[1] Among diffuse astrocytic and oligodendroglial tumors, isocitrate dehydrogenase (IDH) and chromosomal 1p/19q codeletion were adopted to define certain entities of the gliomas, on top of the tumor phenotype and histologic grading. These two markers had been shown to strongly associate with distinct prognostic outcomes among gliomas patients.[2],[3],[4],[5],[6],[7],[8],[9] Defining the integrated diagnostic entities of gliomas with the addition of the molecular markers helped to increase of diagnostic objectivity as well as enhancing the biological homogeneity among each of the glioma entities. However, the prognosis of the glioma subgroups defined by IDH mutation and 1p/19q codeletion remained heterogeneous and additional biomarkers have been shown to have extra values for clinical risk stratification of the molecularly defined subgroups.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20]

BRAF is an intracellular serine/threonine kinase component of the mitogen-activated protein kinase pathway.[21] Hotspot mutation in BRAF led to downstream activation of MEK-ERK pathway and subsequent tumorigenesis.[22]BRAF mutation has been described in various brain tumors including gangliogliomas, pleomorphic xanthoastrocytoma, and pediatric low-grade gliomas.[23],[24] The clinical relevance of BRAF mutation has been reported in pediatric low-grade as well as high-grade gliomas.[24],[25],[26] However, the prognostic value of BRAF mutation in adult gliomas in the context of the WHO 2016 classification remains unexplored.

In this study, we evaluated 578 adult infiltrative gliomas for BRAF mutation and analyzed the clinical significances of BRAF mutation in IDH and 1p/19q codeletion-defined subsets of gliomas. We identified the potential additional prognostic values of BRAF mutation in different molecularly defined gliomas entities.


  Materials and Methods Top


Patients, tissue samples, and clinicopathological data

A total of 578 cases of infiltrative gliomas, Grades II, III, and IV, diagnosed between 1990 and 2014 with formalin-fixed paraffin-embedded tissue available were retrieved from the tissue archive of the Department of Anatomical and Cellular Pathology, Prince of Wales Hospital (Hong Kong, China) and Department of Neurosurgery, Huashan Hospital (Shanghai, China). Tumor sections were stained with hematoxylin and eosin and reviewed by two senior neuropathologists (HKN and HC). Histological classification and grading were assigned according to the WHO 2016 classification.[1] Patient demographics and clinical follow-up data were retrieved from the respective institutional medical record systems. The cohort was partially overlapped with previous studies.[15],[18],[27] This study was approved by the Ethics Committee of Shanghai Huashan Hospital (No. 2017-405) and the New Territories East Cluster-Chinese University of Hong Kong Ethics Committee (No. CRE-2011.087).

Mutational analysis for isocitrate dehydrogenase and BRAF

Mutations of IDH and BRAF were examined by direct sequencing as described previously.[9],[10],[12],[18],[24],[27] Briefly, tissues from representative area of tumor content of at least 70% were scrapped off from deparaffinized sections and treated in 10 mM Tris-HCL buffer (pH 8.5) with proteinase K at a final concentration of 2 μg/μL at 55°C for 2–18 h and then 98°C for 10 min. The cell lysate was centrifuged, and supernatant was collected and used for subsequent polymerase chain reaction (PCR) amplification. PCR products were then treated with exonuclease I and alkaline phosphatase (Takara, Japan) at 37°C for 15 min and then at 80°C for 15 min. Sequencing was performed using BigDye Terminator Cycle Sequencing kit v1.1 (Life Technologies). The products were resolved in Genetic Analyzer 3130xl and analyzed by Sequencing Analysis software. All base changes were confirmed by sequencing of a newly amplified fragment.

Fluorescence in situ hybridization for chromosome 1p/19q codeletion

Chromosome 1p and 19q codeletion were evaluated by fluorescence in situ hybridization as reported previously.[10],[14],[28],[29] The loci examined for 1p and 19q were 1p36.3 (RP11-62M23 labeled red)/1q25.3-q31.1 (RP11-162L13 labeled green) and 19q13.3 (CTD-2571L23 labeled red)/19p12 (RP11-420K14 labeled green), respectively. Locus-specific probes for chromosome 1 and 19 were generated from bacterial artificial chromosome clones using nick translation with the presence of Spectrum Orange deoxyuridine triphosphate (dUTP) or Spectrum Green dUTP. The labeled probes were then mixed with cot-1 DNA (Life Technologies) in Hybrisol VI solution (Appligene Oncor, Graffenstaden, France). Four-μm thick formalin-fixed, paraffin embedded tissue sections were deparaffinized by xylene and treated with 1M sodium thiocyanate at 80°C for 10 min, followed with tissue digestion by pepsin solution at 37°C for 20–30 min. Sections were then rinsed in milli-Q water and dehydrated. The fluorescence in situ hybridization probes was applied to the digested tissue sections and denature. The sections were incubated at 37°C overnight for 16 h. After overnight hybridization, sections were washed in 1.5 M urea in 0.1X saline sodium citrate at 48°C for 30 min, followed by 2X saline sodium citrate at 48°C for 5 min. Sections were then counterstained with Vectashield mounting medium containing 4',6-diamidino-2-phenylindole (DAPI; Vector Laboratories) and evaluated under a Zeiss Axioplan fluorescence microscope (Carl Zeiss Microscopy LLC, NY, USA). Fluorescent signals in at least 100 nonoverlapping nuclei were evaluated. 1p loss or 19q loss were defined as more than 25% of counted nuclei showing target (red) to reference (green) signal ratio of 1:2.[28],[29],[30]

Histomolecular groups

The cohort was evaluated for histology, IDH mutation and 1p/19q codeletion and assigned to Groups I to V. Group I consisted of Grades II and III oligodendrogliomas, IDH-mutant and 1p/19q-codeleted. Group II consisted of Grades II and III astrocytomas, IDH-mutant. Group III consisted of Grades II and III astrocytomas, IDH-wildtype. Group IV consisted of glioblastomas, IDH-mutant. Group V consisted of glioblastomas, IDH-wild type. The prognostic value of BRAF mutation was analyzed in each of the histomolecular groups.

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistic 20 (IBM Corporation, NY, USA). The association between molecular markers and clinical parameters were examined by Chi-square test or Fisher's exact test, whichever appropriate. Overall survival (OS) was defined as the time between diagnosis and death or last follow-up. Survival curves were constructed by Kaplan–Meier method. Log-rank test was used to compare survival distribution between groups. Multivariable analysis was conducted by Cox proportional hazards model. P < 0.05 (two-sided) was considered statistically significant.


  Results Top


Cohort characteristics

We have examined 578 infiltrative gliomas of Grades II, III, and IV and classified the tumors according to the WHO 2016 classification of central nervous system tumors.[1] The cohort consisted of 56 (9.7%) diffuse astrocytomas, IDH-mutant; 60 (10.4%) diffuse astrocytomas, IDH-wild type; 26 (4.5%) anaplastic astrocytomas, IDH-mutant; 60 (10.4%) anaplastic astrocytomas, IDH-wild type; 22 (3.8%) oligodendrogliomas, IDH-mutant, and 1p/19q-codeleted; 14 (2.4%) anaplastic oligodendrogliomas, IDH-mutant, and 1p/19q-codeleted; 42 (7.3%) glioblastomas, IDH-mutant; and 298 (51.6%) glioblastomas, IDH-wild type. The cases were classified into histomolecular groups and there are 36 (6.2%) cases in Group I (oligodendrogliomas, IDH-mutant, and 1p/19q-codeleted), 82 (14.2%) cases in Group II (astrocytomas, IDH-mutant), 120 (20.8%) cases in Group III (astrocytomas, IDH-wild type), 42 (7.3%) cases in Group IV (glioblastomas, IDH-mutant), and 298 (51.6%) cases in Group V (glioblastomas, IDH-wild type). The mean and median ages of the patients were 44.9 years and 45.5 years, respectively, ranging from 19 to 79 years. The male to female ratio was 1.58. Fifty (8.7%) tumors affected midline structures of the central nervous system including thalamus in 17 cases, ventricle in 10 cases, cerebellum in 6 cases, spinal cord in 7 cases, brainstem in 4 cases, basal ganglia in 2 cases, and each for hypothalamus, pineal gland, and suprasellar region. Survival data were available in 305 patients (52.8%). The median follow-up was 8.4 years. The mean and median OS were 5.8 and 2.7 years, respectively.

BRAF mutation

The overall mutation rate of BRAF-V600E was 5.9% (34 out of 578) across the whole cohort, including 1 case of diffuse astrocytoma, IDH-mutant, 5 cases of diffuse astrocytoma, IDH-wild type, 3 cases of anaplastic astrocytomas, IDH-mutant, 4 cases of anaplastic astrocytomas, IDH-wild type, and 21 cases of glioblastomas, IDH-wild type. The BRAF mutation rates in Group II, III, and V were 4.9%, 7.5%, and 7%, respectively [Table 1]. BRAF mutation was associated with younger age in patients with infiltrative gliomas. The mean and median ages of patients with BRAF mutated gliomas were 33.5 years and 27 years, respectively, comparing with 45.6 years and 46 years of BRAF wild-type gliomas (P < 0.001). The BRAF mutation frequency was also different between patient genders and seemed to be higher in female patients. The mutation was found in 21 out of 224 female patients (61.8%) and 13 out of 354 male patients (38.2%) (P = 0.005). Majority (88.2%) of the BRAF mutated gliomas (30/34) were involving nonmidline structures including 11 cases in temporal lobe, 9 cases in frontal lobe, 2 cases in parietal lobe, 1 case in occipital lobe, 1 case in corpus collosum, 1 case in skull base, and 5 cases affecting more than onecerebral lobes. The other 11.8% of the BRAF mutated gliomas (4/34) involved midline structures including 2 cases in spinal cord, 1 case in thalamus and 1 case in third ventricle.
Table 1: Clinical characteristics and BRAF mutation status of diffuse gliomas

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Survival analysis

Univariate analyses according to the clinicopathologic variables and BRAF mutation were shown in [Table 2]. Older patient age (P = 0.025) and male gender (P = 0.007) were associated with a poorer prognosis in terms of OS. Tumors affecting midline structure were also associated with shorter OS (median OS 1.1 years) than those not involving midline structures (median OS 3.4 years) (P < 0.001). In terms of histologic grade, the median OS of Grade II, III and IV gliomas were 10.6 years, 1.8 years, and 1.2 years, respectively (P < 0.001). Univariate analysis also showed that the histomolecular groups could stratify the infiltrative gliomas into 5 prognostic groups (P < 0.001) [Figure 1]. Across the cohort, median OS of BRAF mutated glioma patients was 4.3 years and that of BRAF wild-type glioma patients was 2.6 years [Figure 2]A. The prognostic value of BRAF mutation in infiltrative gliomas was further analyzed in different histomolecular groups [Figure 2]B, [Figure 2]C, [Figure 2]D. Among Group II gliomas, i.e., astrocytomas, IDH-mutant, patients with BRAF mutant tumor trended to have poorer prognosis with median OS of 2 years, comparing to BRAF wild-type tumor with median OS of 6.9 years [Figure 2]B. Among Group III gliomas, i.e., astrocytomas, IDH-wild-type, patients with BRAF mutant tumor trended to have a better prognosis with median OS of 10.7 years, comparing to BRAF wild-type tumor with median OS of 1.9 years [Figure 2]C. Among Group V gliomas, i.e., glioblastomas, IDH-wild type, and BRAF mutation were associated with significantly longer OS (median OS 3.6 years) comparing to BRAF wild type (median OS 0.9 years) [Figure 2]D. The independent prognostic value of BRAF mutation was further tested by multivariable analysis in each of the histomolecular groups by adjusting for patient age, gender, and tumor location [Table 3]. In Group II gliomas, BRAF mutation trended to worse prognosis with hazard ratio (HR) of 2.33. BRAF mutation was an independent favorable prognostic marker in Group III gliomas with HR of 0.31 (P = 0.04). BRAF mutation also trended to favorable prognosis in Group V gliomas with HR of 0.44.
Table 2: Univariate analysis of diffuse gliomas

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Figure 1: Survival comparison of Groups I to V gliomas

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Figure 2: Kaplan-Meier survival analysis of BRAF mutation across the whole cohort of adult infiltrative gliomas (a) and in each of the histo-molecular groups (b-d). Patients with BRAF mutant glioma trended to poorer prognosis among Group II gliomas (astrocytomas, isocitrate dehydrogenase mutant) (b). Patients with BRAF mutant glioma trended to better prognosis among Group III gliomas (astrocytomas, isocitrate dehydrogenase-wildtype) (c), and had significantly longer overall survival among Group V gliomas (glioblastomas, isocitrate dehydrogenase wild type)

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Table 3: Multivariable analysis in different histo-molecular groups

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  Discussion Top


In the revised 4th edition of the WHO 2016 classification of central nervous system tumors, molecular markers have been incorporated into the classification system of gliomas in addition to histologic classification and WHO grade to provide integrated diagnostic reporting.[1] The favorable prognostic values of IDH mutation and 1p/19q codeletion in infiltrative gliomas have been extensively demonstrated in the literature and therefore the prognostication could be naturally extrapolated to the biomarker-defining histologic groups.[2],[3],[4],[5],[6],[7],[8],[9],[12] Various molecular markers have been investigated for their prognostic classification value on top of IDH mutation and 1p/19q codeletion before and after the publication of the WHO 2016 classification of central nervous system tumors.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] In the current study, we examined BRAF mutation in a large cohort of infiltrative gliomas, with the aim to delineate the prognostic role of BRAF mutation in gliomas in the WHO 2016 integrated diagnostic entities.

Across our cohort of adult Grades II to IV infiltrative gliomas, mutation rate of BRAF was 5.9%, a frequency comparable to those in previously reported cohorts.[23],[31],[32],[33],[34] Nevertheless, BRAF mutation could be detected in all grades of adult infiltrative gliomas and was associated with younger patient age. The majority (30 out of 34) of the BRAF mutation was identified in IDH-wild-type gliomas while four cases were found in IDH mutant gliomas, all of which were IDH- mutant lower-grade astrocytomas. Notably, the cooccurrence of IDH and BRAF mutations was reported previously in a study by Badiali et al.[33] Apart from a case of IDH-mutant and 1p/19q-codeleted anaplastic oligodendroglioma showing BRAF-V600E mutation, the group also identified 17 infiltrative gliomas showing both IDH mutation and BRAF- KIAA1549 fusion, with 15 cases being oligodendroglial tumors. These findings together with ours suggested that the Ras-RAF-ERK signaling pathway could be potentially dysregulated in a small subset of IDH-mutant gliomas. Our study additionally examined the prognostic value of BRAF mutation in IDH-mutant gliomas which was previously unexplored. Among the 75 Group II gliomas (astrocytomas and IDH-mutant), the median OS of the 4 BRAF-mutant tumors was 2 years, comparing to 6.9 years for BRAF-wild-type tumors (P = 0.214). Multivariable analysis within the Group II gliomas also showed a trend of poorer prognosis for patients with BRAF mutant tumors with HR of 2.33 (P = 0.17). The prognostic value of BRAF mutation among IDH- mutant gliomas warrants further investigation in the future with an expanded cohort of IDH mutant gliomas.

BRAF mutation seemed to be a potentially favorable prognosticator in IDH-wild-type lower-grade astrocytomas and IDH- wild-type glioblastomas. Among the 104 Group III gliomas (astrocytomas and IDH- wild type), the median OS of the 9 BRAF-mutant tumors was 10.7 years, as compared to 1.9 years for BRAF-wild-type tumors (P = 0.145). Multivariable analysis within Group III gliomas confirmed the independent favorable prognostic value of BRAF mutation with HR 0.31 (P = 0.04). Among the 77 Group V gliomas (glioblastomas and IDH-wild type), the median OS of the 12 BRAF-mutant glioblastomas was 3.6 years, as compared to 0.9 years for BRAF-wild-type glioblastomas (P = 0.11). Multivariable analysis within the Group V tumors also demonstrated the trend of better survival for patients with BRAF mutant glioblastomas comparing to those with BRAF wild-type glioblastomas with HR of 0.44 (P = 0.077). Our findings regarding the association between BRAF mutation and favorable clinical outcome in adult IDH-wild-type infiltrative gliomas corroborated with the previous observations from smaller-sized cohorts,[31],[35] and together with the strong evidence of clinical significance of BRAF mutation in pediatric glioma patients including association with unfavorable survival, poor response to chemoradiation therapy, and malignant transformation to high-grade glioma,[24],[25],[26] further suggested that BRAF mutational analysis should be implemented into the clinicopathological risk stratification for patients with infiltrative gliomas. Importantly, various case reports and studies had demonstrated the effectiveness of treating pediatric patients with BRAF mutant gliomas using BRAF-V600E specific inhibitor such as vemurafenib and dabrafenib,[36],[37],[38],[39],[40],[41],[42] although some patients progress on single-agent therapy with the specific inhibitor,[43] suggesting the potential benefit of combination therapy using BRAF and MEK inhibitors in treating patients with BRAF mutant gliomas.[44]

We have examined BRAF mutation in a large cohort of adult infiltrative gliomas and evaluated the prognostic relevance of this biomarker with respect to the WHO 2016 diagnostic entities. BRAF mutation appears to mark out a small subset of adult infiltrative gliomas with the distinct clinical outcome. Mutational analysis of BRAF can potentially contribute to the clinical risk stratification in the management of glioma patients in the context of the WHO 2016 classification.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]


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