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Discovery of a rare...
Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib
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- Deland, Lily (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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- Keane, Simon (author)
- University of Skövde,Högskolan i Skövde,Institutionen för hälsovetenskaper,Forskningsmiljön hälsa, hållbarhet och digitalisering,Translationell medicin TRIM, Translational Medicine
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- Bontell, Thomas Olsson (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology
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- Sjögren, Helene, 1968 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Institute of Biomedicine
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- Fagman, Henrik, 1975 (author)
- Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
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- Øra, Ingrid (author)
- Lund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Childhood Cancer Research Unit,Forskargrupper vid Lunds universitet,Cancercellers evolution,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups,Pathways of cancer cell evolution,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Department of Clinical Sciences, Lund University Hospital, Sweden ; HOPE/ITCC Phase I/II Trial Unit, Pediatric Oncology, Karolinska Hospital, Stockholm, Sweden
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- De La Cuesta, Esther (author)
- Pharmaceuticals, Global Medical Affairs–Oncology, Bayer U.S, Whippany, United States,Bayer Corporation, USA
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- Tisell, Magnus (author)
- Department of Clinical Neuroscience and Rehabilitation, Sahlgrenska University Hospital, Gothenburg, Sweden
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- Nilsson, Jonas A (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Sahlgrenska Cancer Center, Department of Laboratory Medicine Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Sahlgrenska Centrum för Cancerforskning (SCCR),Department of Laboratory Medicine,Sahlgrenska Center for Cancer Research (SCCR)
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- Ejeskär, Katarina, 1969- (author)
- University of Skövde,Högskolan i Skövde,Institutionen för hälsovetenskaper,Forskningsmiljön hälsa, hållbarhet och digitalisering,Translationell medicin TRIM, Translational Medicine
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- Sabel, Magnus, 1966 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Childhood Cancer Centre, Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics
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- Abel, Frida, 1974 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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(creator_code:org_t)
- 2021-04-05
- 2021
- English.
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In: Cancer Biology & Therapy. - : Taylor & Francis. - 1538-4047 .- 1555-8576. ; 22:3, s. 184-195
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Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- GKAP1
- larotrectinib
- NTRK2
- pediatric brain tumor
- pLGG
- precision medicine
- TRKB; fusion gene
- Translationell medicin TRIM
- Translational Medicine TRIM
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Deland, Lily
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Keane, Simon
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Bontell, Thomas ...
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Sjögren, Helene, ...
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Fagman, Henrik, ...
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Øra, Ingrid
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De La Cuesta, Es ...
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Tisell, Magnus
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Nilsson, Jonas A
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Ejeskär, Katarin ...
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Sabel, Magnus, 1 ...
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Abel, Frida, 197 ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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Cancer Biology & ...
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University of Skövde
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Lund University
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University of Gothenburg