Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors
| Autor: | Patrick N. Harter, Martin U. Schuhmann, Laura Gieldon, Christian Brandts, Joachim P. Steinbach, Hanno Glimm, Marlies Wagner, Michael W. Ronellenfitsch, Marcos Tatagiba, Martina Kirchner, Michel Mittelbronn, Barbara Hutter, Victor-Felix Mautner, Wilko Weichert, David E. Reuss, Andreas von Deimling, Benedikt Brors, Jens Schittenhelm, Volker Endris, Evelin Schröck, Gerhard Marquardt, Christoph Heining, Albrecht Stenzinger, Stefan Fröhling |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
0301 basic medicine Oncology medicine.medical_specialty Receptor ErbB-2 Mutation Missense Context (language use) Schwannoma Lapatinib Nerve Sheath Neoplasms 03 medical and health sciences 0302 clinical medicine Internal medicine Humans Medicine Neurofibroma Neurofibromatosis type 2 Neurofibromatosis Schwannomatosis business.industry Cancer General Medicine medicine.disease 030104 developmental biology Amino Acid Substitution 030220 oncology & carcinogenesis Female Clinical Medicine business Neurilemmoma medicine.drug |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | BACKGROUND: Neurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking. METHODS: We used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs. RESULTS: Whole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns. CONCLUSION: These findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications. FUNDING: This work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program. |
| Databáze: | OpenAIRE |
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