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 - Funding Information:
The authors thank the DKFZ-HIPO Sample Processing Laboratory and the DKFZ Genomics and Proteomics Core Facility for technical support. We also thank Katja Beck, Viktoria Fischer, Kar-olin Willmund, and Peter Lichter for infrastructure and program development within DKFZ-HIPO. FDG-PET/MRI studies were performed at the Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany. The authors thank Sergios Gatidis for critical review of the manuscript. MM is supported by grant FNR PEARL P16/BM/11192868 from the Luxembourg National Research Fond. This work was supported by grant H021 from DKFZ-HIPO. MWR and PNH received fellowships from University Cancer Center Frankfurt, and MWR received funding from the Frankfurt Research Funding Clinician Scientist Program.
Funding Information:
FUNDING. This work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.
Funding Information:
Authorship note: JPS, DER, HG, AS, and SF share last authorship. Conflict of interest: MWR has received research funding from UCB. VE has collected personal fees from AstraZeneca, Merck Sharp & Dohme, Novartis, and Thermo Fisher Scientific, with other support from Illumina. WW has collected personal fees from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda, as well as research funding from Bristol-Myers Squibb, Bruker, Merck Sharp & Dohme, and Roche. AVD and DR have licensed an NF1 antibody to Cell Marque. JPS has a consulting or advisory board membership with, or has received honoraria or travel or accommodation expenses from Abbvie, Medac, Novocure, Roche, and UCB. AS has consulting or advisory board membership with AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, Novartis, Seattle Genomics, Takeda, and Thermo Fisher Scientific; received honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Illumina, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genomics, Takeda, and Thermo Fisher Scientific; and received research funding from Bayer, Bristol-Myers Squibb, and Chugai. SF has a consulting or advisory board membership with Bayer and Roche; received honoraria from Amgen, Eli Lilly, PharmaMar, and Roche; received research funding from Astra-Zeneca, Pfizer, and PharmaMar; and received travel or accommodation expenses from Amgen, Eli Lilly, PharmaMar, and Roche. Copyright: © 2020, American Society for Clinical Investigation. Submitted: June 6, 2019; Accepted: January 30, 2020; Published: April 13, 2020. Reference information: J Clin Invest. 2020;130(5):2488–2495. https://doi.org/10.1172/JCI130787.
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 -