Alterations in BRAF gene, and enhanced mTOR and MAPK signaling in dysembryoplastic neuroepithelial tumors (DNTs).
Recently, BRAF V600E mutation, and activation of mTOR and MAPK pathways have been identified in various glial/glioneuronal tumors. Dysembryoplastic neuroepithelial tumors (DNTs) are epilepsy-associated glioneuronal neoplasms which have not been analyzed extensively in this respect.



Sequencing for BRAF V600E mutation, analysis of BRAF copy number by qRT-PCR, and immunohistochemistry for mTOR (p-S6, p-4EBP1) and MAPK (p-MAPK) pathways were performed.



Sixty-four DNTs were identified, accounting for 15.1% of patients with drug-refractory epilepsy (mean age: 15.5 years). Duration of seizures ranged from 1 to 22 years. BRAF V600E mutation was identified in 3.7% of DNTs, while BRAF copy number gain was observed in 33.3%. mTOR-pathway activation indicated by p-S6 or p-4EBP1 immunopositivity was seen in 89.7% cases. Interestingly, p-S6 positivity was also seen in adjacent dysplastic cortex. p-MAPK immunopositivity was seen in 50% cases. MAPK and mTOR pathway activation was independent of BRAF alterations. All patients that underwent incomplete resection had Engel grade II-III outcomes (p<0.001).



BRAF alterations are frequent in DNTs, particularly BRAF copy number gain which is being reported for the first time in these tumors. Evidence of activation of mTOR and MAPK pathways suggests a role for altered signalling in DNT pathogenesis, and will pave the way for development of targeted therapies, particularly relevant for patients having persistent seizures after incomplete resection.
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Aanchal
A
Kakkar
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Atreye
A
Majumdar
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Anupam
A
Kumar
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
Manjari
M
Tripathi
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Pankaj
P
Pathak
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Mehar C
MC
Sharma
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Vaishali
V
Suri
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.
Vivek
V
Tandon
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.
Sarat P
SP
Chandra
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. Electronic address: sarkar.chitra@gmail.com.
Chitra
C
Sarkar
D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D000069279:Drug Resistant Epilepsy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009154:Mutation; D018302:Neoplasms, Neuroepithelial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
C546842:MTOR protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
BRAF; Dysembryoplastic neuroepithelial tumor; Epilepsy; MAPK; mTOR