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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

Deland, Lily ; Keane, Simon ; Olsson Bontell, Thomas ; Sjögren, Helene ; Fagman, Henrik ; Øra, Ingrid LU ; De La Cuesta, Esther ; Tisell, Magnus ; Nilsson, Jonas A LU and Ejeskär, Katarina , et al. (2021) In Cancer Biology & Therapy 22(3). p.184-195
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Biology & Therapy
volume
22
issue
3
pages
184 - 195
publisher
Landes Bioscience
external identifiers
  • pmid:33820494
  • scopus:85103915136
ISSN
1538-4047
DOI
10.1080/15384047.2021.1899573
language
English
LU publication?
yes
id
e574577d-d6ae-484f-8bcf-64f794e3120f
date added to LUP
2021-04-09 20:48:03
date last changed
2024-03-08 10:52:36
@article{e574577d-d6ae-484f-8bcf-64f794e3120f,
  abstract     = {{<p>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.</p>}},
  author       = {{Deland, Lily and Keane, Simon and Olsson Bontell, Thomas and Sjögren, Helene and Fagman, Henrik and Øra, Ingrid and De La Cuesta, Esther and Tisell, Magnus and Nilsson, Jonas A and Ejeskär, Katarina and Sabel, Magnus and Abel, Frida}},
  issn         = {{1538-4047}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{3}},
  pages        = {{184--195}},
  publisher    = {{Landes Bioscience}},
  series       = {{Cancer Biology & Therapy}},
  title        = {{Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib}},
  url          = {{http://dx.doi.org/10.1080/15384047.2021.1899573}},
  doi          = {{10.1080/15384047.2021.1899573}},
  volume       = {{22}},
  year         = {{2021}},
}