RESUMO
Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.
Assuntos
Metilação de DNA , Neoplasias da Orelha/genética , Mutação , Neurilemoma/genética , Neoplasias da Coluna Vertebral/genética , Vestíbulo do Labirinto , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Linhagem Celular Tumoral , Análise Mutacional de DNA , DNA de Neoplasias , Exoma , Feminino , Fusão Gênica , Genoma Humano , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Neoplásico , Análise de Sequência de DNA , Análise de Sequência de RNA , Serina Endopeptidases/genéticaRESUMO
We report the case of a seventy-five year old woman with a sporadic primary malignant intracerebral nerve sheath tumor (MINST). These tumors fall within the spectrum of malignant peripheral nerve sheath tumors (MPNST) but confirming the diagnosis of a MINST can be difficult due to its rarity and unusual intraparenchymal location. Radiographically, MINST's mimic malignant glioma and should be considered in the differential diagnosis of enhancing cerebral lesions. In this report, we present a comprehensive panel of histological, immunohistochemical, ultrastructural, and genetic considerations that may be used to diagnosis MINST based on their similarities to MPNSTs and brain parenchyma location.
