Aanchal Kakkar1, Atreye Majumdar1, Anupam Kumar1, Manjari Tripathi2, Pankaj Pathak1, Mehar C Sharma1, Vaishali Suri1, Vivek Tandon3, Sarat P Chandra3, Chitra Sarkar4. 1. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. 2. Department of Neurology, All India Institute of Medical Sciences, New Delhi, India. 3. Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India. 4. Department of Pathology, All India Institute of Medical Sciences, New Delhi, India. Electronic address: sarkar.chitra@gmail.com.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
OBJECTIVE: Recently, BRAFV600E 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. METHODS: Sequencing for BRAFV600E mutation, analysis of BRAF copy number by qRT-PCR, and immunohistochemistry for mTOR (p-S6, p-4EBP1) and MAPK (p-MAPK) pathways were performed. RESULTS: 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. BRAFV600E 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). CONCLUSION: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.
Authors: Thomas J Stone; Angus Keeley; Alex Virasami; William Harkness; Martin Tisdall; Elisa Izquierdo Delgado; Alice Gutteridge; Tony Brooks; Mark Kristiansen; Jane Chalker; Lisa Wilkhu; William Mifsud; John Apps; Maria Thom; Mike Hubank; Tim Forshew; J Helen Cross; Darren Hargrave; Jonathan Ham; Thomas S Jacques Journal: Acta Neuropathol Date: 2017-10-20 Impact factor: 17.088
Authors: Anika Bongaarts; Avanita S Prabowo; Andrea Arena; Jasper J Anink; Roy J Reinten; Floor E Jansen; Wim G M Spliet; Maria Thom; Roland Coras; Ingmar Blümcke; Katarzyna Kotulska; Sergiusz Jozwiak; Wieslawa Grajkowska; Figen Söylemezoğlu; José Pimentel; Antoinette Y N Schouten-van Meeteren; James D Mills; Anand M Iyer; Erwin A van Vliet; Angelika Mühlebner; Eleonora Aronica Journal: Oncotarget Date: 2018-06-15