TY - JOUR
T1 - Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors
AU - Ronellenfitsch, Michael W.
AU - Harter, Patrick N.
AU - Kirchner, Martina
AU - Heining, Christoph
AU - Hutter, Barbara
AU - Gieldon, Laura
AU - Schittenhelm, Jens
AU - Schuhmann, Martin U.
AU - Tatagiba, Marcos
AU - Marquardt, Gerhard
AU - Wagner, Marlies
AU - Endris, Volker
AU - Brandts, Christian H.
AU - Mautner, Victor Felix
AU - Schröck, Evelin
AU - Weichert, Wilko
AU - Brors, Benedikt
AU - von Deimling, Andreas
AU - Mittelbronn, Michel
AU - Steinbach, Joachim P.
AU - Reuss, David E.
AU - Glimm, Hanno
AU - Stenzinger, Albrecht
AU - Fröhling, Stefan
N1 - Publisher Copyright:
© 2020 American Society for Clinical Investigation. All rights reserved.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084220594&partnerID=8YFLogxK
U2 - 10.1172/JCI130787
DO - 10.1172/JCI130787
M3 - Article
C2 - 32017710
AN - SCOPUS:85084220594
SN - 0021-9738
VL - 130
SP - 2488
EP - 2495
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -