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

  • Luxembourg Center of Neuropathology
May 01, 2020 By:
  • Ronellenfitsch MW
  • Harter PN
  • Kirchner M
  • Heining C
  • Hutter B
  • Gieldon L
  • Schittenhelm J
  • Schuhmann MU
  • Tatagiba M
  • Marquardt G
  • Wagner M
  • Endris V
  • Brandts CH
  • Mautner VF
  • Schrock E
  • Weichert W
  • Brors B
  • von Deimling A
  • Mittelbronn M
  • Steinbach JP
  • Reuss DE
  • Glimm H
  • Stenzinger A
  • Frohling S.

BACKGROUNDNeurofibroma/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.METHODSWe used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs.RESULTSWhole-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.CONCLUSIONThese findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications.FUNDINGThis work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.

2020 May. J Clin Invest.130(5):2488-2495.
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