BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications

Dora Dias-Santagata,Azra H Ligon,Darrell R Borger,David N Louis,Quynh Lam,Keith L Ligon,Tracy T Batchelor,Kathy Vernovsky,Sandro Santagata,Natalie Vena,A John Iafrate,Jochen K Lennerz

doi:10.1371/journal.pone.0017948

Dora Dias-Santagata, Azra H Ligon + Show 10 more

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Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs.

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Pleomorphic xanthoastrocytoma (PXA) is an uncommon lowgrade glial neoplasm of the central nervous system that most frequently affects children and young adults [1,2,3,4,5,6]
Glioma Cases Profiled with SNaPshot To investigate the genetic changes underlying pleomorphic xanthoastrocytomas, we identified relevant tumors that were resected between 1996 and 2010 at Massachusetts General Hospital, Brigham and Women’s Hospital, and Children’s Hospital Boston
We retrieved cases that were thought to be unequivocal grade II PXA during the clinical evaluation of the surgical pathology specimens as well as tumors that demonstrated most of the features of PXA and were thought to be ‘‘consistent with PXA.’’ In addition, we identified cases of PXA with anaplastic features such as necrosis and increased mitoses as well as cases of giant cell glioblastoma

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Introduction

Pleomorphic xanthoastrocytoma (PXA) is an uncommon lowgrade glial neoplasm of the central nervous system that most frequently affects children and young adults [1,2,3,4,5,6]. The presence of eosinophilic granular bodies and the compact, predominantly noninfiltrating nature of PXA can introduce pilocytic astrocytoma into the differential diagnosis [5]. The histopathologic diagnosis of PXA can often be accomplished readily when the histologic findings are carefully considered in light of the clinical and radiological features, the diagnosis can be challenging and confusion with other neoplasms can occur [10]. A reproducible ancillary diagnostic marker for PXA would, be of significant clinical use

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