ERBB2/HER2 mutations are transforming and therapeutically targetable in leukemia.
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ABSTRACT:
SUBMITTER: Joshi SK
PROVIDER: S-EPMC7515826 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
ERBB2/HER2 mutations are transforming and therapeutically targetable in leukemia.
Joshi Sunil K SK Keck Jamie M JM Eide Christopher A CA Bottomly Daniel D Traer Elie E Tyner Jeffrey W JW McWeeney Shannon K SK Tognon Cristina E CE Druker Brian J BJ
Leukemia 20200504 10
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Project description: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.
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