Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors

Michael W. Ronellenfitsch*, Patrick N. Harter, Martina Kirchner, Christoph Heining, Barbara Hutter, Laura Gieldon, Jens Schittenhelm, Martin U. Schuhmann, Marcos Tatagiba, Gerhard Marquardt, Marlies Wagner, Volker Endris, Christian H. Brandts, Victor Felix Mautner, Evelin Schröck, Wilko Weichert, Benedikt Brors, Andreas von Deimling, Michel Mittelbronn, Joachim P. SteinbachDavid E. Reuss, Hanno Glimm, Albrecht Stenzinger, Stefan Fröhling

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2488-2495
Number of pages8
JournalJournal of Clinical Investigation
Volume130
Issue number5
DOIs
Publication statusPublished - 1 May 2020

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