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Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib
Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translationell medicin TRIM, Translational Medicine)ORCID iD: 0000-0002-0471-6896
Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
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2021 (English)In: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 22, no 3, p. 184-195Article in journal (Refereed) Published
Abstract [en]

Here we report a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment. Routine clinical examination classified the tumor as a BRAF-negative pilocytic astrocytoma. Copy-number variation profiling of fresh frozen tumor material identified two duplications in 9q21.32–33 leading to breakpoints within the GKAP1 and NTRK2 genes. RT-PCR Sanger sequencing revealed a GKAP1-NTRK2 exon 10–16 in-frame fusion, generating a putative fusion protein of 658 amino acids with a retained tyrosine kinase (TK) domain. Functional analysis by transient transfection of HEK293 cells showed the GKAP1-NTRK2 fusion protein to be activated through phosphorylation of the TK domain (Tyr705). Subsequently, downstream mediators of the MAPK- and PI3K-signaling pathways were upregulated in GKAP1-NTRK2 cells compared to NTRK2 wild-type; phosphorylated (p)ERK (3.6-fold), pAKT (1.8- fold), and pS6 ribosomal protein (1.4-fold). Following these findings, the patient was enrolled in a clinical trial and treated with the specific TRK-inhibitor larotrectinib, resulting in the arrest of tumor growth. The patient’s condition is currently stable and the quality of life has improved significantly. Our findings highlight the value of comprehensive clinical molecular screening of BRAF-negative pediatric low-grade gliomas, to reveal rare fusions serving as targets for precision therapy. 

Place, publisher, year, edition, pages
Taylor & Francis, 2021. Vol. 22, no 3, p. 184-195
Keywords [en]
GKAP1, larotrectinib, NTRK2, pediatric brain tumor, pLGG, precision medicine, TRKB; fusion gene
National Category
Cancer and Oncology
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-19649DOI: 10.1080/15384047.2021.1899573ISI: 000636984900001PubMedID: 33820494Scopus ID: 2-s2.0-85103915136OAI: oai:DiVA.org:his-19649DiVA, id: diva2:1546498
Funder
European Commission, PR2017-0029 PR2019-0079
Note

CC BY-NC-ND 4.0

© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.

Available from: 2021-04-22 Created: 2021-04-22 Last updated: 2022-10-26Bibliographically approved

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Keane, SimonEjeskär, Katarina

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