NTRK fusions in osteosarcoma are rare and non‐functional events
Abstract Neurotrophic tyrosine receptor kinase (NTRK) fusions are promising molecular targets that have been described in a broad range of malignant tumours. Fusions commonly lead to the expression of chimeric proteins with constitutive tyrosine kinase activation that drives tumorigenesis. Despite a...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Wiley
2020-04-01
|
Series: | The Journal of Pathology: Clinical Research |
Subjects: | |
Online Access: | https://doi.org/10.1002/cjp2.158 |
id |
doaj-bdb9927c6bec41f191765c2ee1a038bd |
---|---|
record_format |
Article |
spelling |
doaj-bdb9927c6bec41f191765c2ee1a038bd2020-11-25T02:55:18ZengWileyThe Journal of Pathology: Clinical Research2056-45382020-04-016210711210.1002/cjp2.158NTRK fusions in osteosarcoma are rare and non‐functional eventsBaptiste Ameline0Karim H Saba1Michal Kovac2Linda Magnusson3Olaf Witt4Stefan Bielack5Michaela Nathrath6Karolin H Nord7Daniel Baumhoer8Bone Tumour Reference Center at the Institute of Pathology University and University Hospital Basel Basel SwitzerlandDepartment of Laboratory Medicine, Division of Clinical Genetics Lund University Lund SwedenBone Tumour Reference Center at the Institute of Pathology University and University Hospital Basel Basel SwitzerlandDepartment of Laboratory Medicine, Division of Clinical Genetics Lund University Lund SwedenCoordinator INFORM Program, Hopp Children's Cancer Center, German Cancer Research Center, University Hospital Heidelberg Heidelberg GermanyCooperative Osteosarcoma Study Group, Stuttgart Cancer Center, Klinikum Stuttgart – Olgahospital, Pediatrics 5 (Oncology, Hematology, Immunology) Stuttgart GermanyDepartment of Pediatrics, Pediatric Oncology Center Technische Universität München Munich GermanyDepartment of Laboratory Medicine, Division of Clinical Genetics Lund University Lund SwedenBone Tumour Reference Center at the Institute of Pathology University and University Hospital Basel Basel SwitzerlandAbstract Neurotrophic tyrosine receptor kinase (NTRK) fusions are promising molecular targets that have been described in a broad range of malignant tumours. Fusions commonly lead to the expression of chimeric proteins with constitutive tyrosine kinase activation that drives tumorigenesis. Despite a low prevalence among most solid tumours (<1%), the first encouraging results with pan‐NTRK tyrosine kinase inhibitors (TKIs) such as larotrectinib or entrectinib stimulated the search for eligible patients. Here, we report the first three cases of osteosarcoma harbouring NTRK fusions, among 113 patients sequenced. It is also the first report on NTRK fusions within a tumour type characterised by highly rearranged genomes and abundant passenger mutations. Whereas the presence of NTRK gene fusions in many tumours is considered to be one of the main driver events for tumour progression, the three chimeric transcripts described here appear non‐functional and likely represent randomly occurring passenger alterations. Particularly in tumours with complex karyotypes, it may therefore be advisable to specifically investigate the fusion transcripts for functional impact before considering targeted treatment approaches using pan‐NTRK TKIs.https://doi.org/10.1002/cjp2.158NTRKtyrosine kinase inhibitorsosteosarcoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Baptiste Ameline Karim H Saba Michal Kovac Linda Magnusson Olaf Witt Stefan Bielack Michaela Nathrath Karolin H Nord Daniel Baumhoer |
spellingShingle |
Baptiste Ameline Karim H Saba Michal Kovac Linda Magnusson Olaf Witt Stefan Bielack Michaela Nathrath Karolin H Nord Daniel Baumhoer NTRK fusions in osteosarcoma are rare and non‐functional events The Journal of Pathology: Clinical Research NTRK tyrosine kinase inhibitors osteosarcoma |
author_facet |
Baptiste Ameline Karim H Saba Michal Kovac Linda Magnusson Olaf Witt Stefan Bielack Michaela Nathrath Karolin H Nord Daniel Baumhoer |
author_sort |
Baptiste Ameline |
title |
NTRK fusions in osteosarcoma are rare and non‐functional events |
title_short |
NTRK fusions in osteosarcoma are rare and non‐functional events |
title_full |
NTRK fusions in osteosarcoma are rare and non‐functional events |
title_fullStr |
NTRK fusions in osteosarcoma are rare and non‐functional events |
title_full_unstemmed |
NTRK fusions in osteosarcoma are rare and non‐functional events |
title_sort |
ntrk fusions in osteosarcoma are rare and non‐functional events |
publisher |
Wiley |
series |
The Journal of Pathology: Clinical Research |
issn |
2056-4538 |
publishDate |
2020-04-01 |
description |
Abstract Neurotrophic tyrosine receptor kinase (NTRK) fusions are promising molecular targets that have been described in a broad range of malignant tumours. Fusions commonly lead to the expression of chimeric proteins with constitutive tyrosine kinase activation that drives tumorigenesis. Despite a low prevalence among most solid tumours (<1%), the first encouraging results with pan‐NTRK tyrosine kinase inhibitors (TKIs) such as larotrectinib or entrectinib stimulated the search for eligible patients. Here, we report the first three cases of osteosarcoma harbouring NTRK fusions, among 113 patients sequenced. It is also the first report on NTRK fusions within a tumour type characterised by highly rearranged genomes and abundant passenger mutations. Whereas the presence of NTRK gene fusions in many tumours is considered to be one of the main driver events for tumour progression, the three chimeric transcripts described here appear non‐functional and likely represent randomly occurring passenger alterations. Particularly in tumours with complex karyotypes, it may therefore be advisable to specifically investigate the fusion transcripts for functional impact before considering targeted treatment approaches using pan‐NTRK TKIs. |
topic |
NTRK tyrosine kinase inhibitors osteosarcoma |
url |
https://doi.org/10.1002/cjp2.158 |
work_keys_str_mv |
AT baptisteameline ntrkfusionsinosteosarcomaarerareandnonfunctionalevents AT karimhsaba ntrkfusionsinosteosarcomaarerareandnonfunctionalevents AT michalkovac ntrkfusionsinosteosarcomaarerareandnonfunctionalevents AT lindamagnusson ntrkfusionsinosteosarcomaarerareandnonfunctionalevents AT olafwitt ntrkfusionsinosteosarcomaarerareandnonfunctionalevents AT stefanbielack ntrkfusionsinosteosarcomaarerareandnonfunctionalevents AT michaelanathrath ntrkfusionsinosteosarcomaarerareandnonfunctionalevents AT karolinhnord ntrkfusionsinosteosarcomaarerareandnonfunctionalevents AT danielbaumhoer ntrkfusionsinosteosarcomaarerareandnonfunctionalevents |
_version_ |
1724716798139432960 |