Abstract
Background: Neurotrophic tyrosine receptor kinase (NTRK) fusion has been detected in rare types of CNS tumours, which can promote tumorigenesis. The efficacy of Trk inhibitor became a significant therapeutic interest. Our aim was to investigate whether Pan-Trk immunohistochemistry (IHC) is a reliable and efficient marker for detecting NTRK-fusion in different brain tumours. Methods: This study included 23 patients diagnosed with different types of CNS tumours. Testing for Pan-Trk IHC with monoclonal Ab (EPR17341) has been performed on all FFPE tissues. Parallelly, NTRK-rearrangements were tested using both DNA and RNA-based next-generation sequencing (NGS) assay using TruSight Onco500 platform. Results: The cohort included eight pilocytic astrocytomas, one oligodendroglioma, six IDHwildtype glioblastomas, four IDHmutant grade four astrocytomas, and one sample of each (astroblastoma, central neurocytoma, medulloblastoma, and liponeurocytoma). The mean age was 35 years; seven cases were in the paediatric age group, and 16 were adult. Pan-Trk expression was detected in 11 (47.8%) tumours, and 12 (52.1%) tumours showed no Pan-Trk expression. Nine Cases (82%) with different Pan-Trk expressions did not reveal NTRK-rearrangement. The other two positively expressed cases (liponeurocytoma and glioblastoma) were found to have NTRK2-fusions (SLC O 5A1-NTRK2, AGBL4-NTRK2, BEND5-NTRK2). All the 12 cases (100%) with no Pan-Trk expression have shown no NTRK-fusions. There was no statistically significant association between Pan-Trk expression and NTRK-fusion (p = 0.217). The detection of NTRK- fusions using NGS had high specificity over NTRK-fusion detection by using Pan-Trk IHC. Conclusion: Pan-Trk IHC is not a suitable tissue-efficient biomarker to screen for NTRK-fusions in CNS tumours, however RNA-based NGS sequencing should be used as an alternative method.
Highlights
The neurotrophic tyrosine receptor kinase (NTRK) is a family member of three genes (NTRK1, NTRK2, NTRK3), which produce tyrosine kinase (TK) proteins (Trk-A, Trk-B, and Trk-C) (1)
Pan-Trk IHC is not a suitable tissue-efficient biomarker to screen for NTRKfusions in CNS tumours, RNA-based next-generation sequencing (NGS) sequencing should be used as an alternative method
These findings suggest that a diagnostic strategy managed by NTRK-fusions biological incidence may be the best effective approach to identify patients with NTRK-fusions
Summary
The neurotrophic tyrosine receptor kinase (NTRK) is a family member of three genes (NTRK1, NTRK2, NTRK3), which produce tyrosine kinase (TK) proteins (Trk-A, Trk-B, and Trk-C) (1) Their receptors are highly expressed in neural tissue, in which they play an important role in neuronal development, proliferation, synaptic plasticity, and cognition and memory (2). They have a similar structure; each consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular kinase domain. Rearrangements in the NTRK gene can result in two genes fusing at the C-terminal TKdomain with N-terminal fusion partner producing altered Trk proteins This fusion may lead to uncontrolled growth of tumour cells (1). Our aim was to investigate whether Pan-Trk immunohistochemistry (IHC) is a reliable and efficient marker for detecting NTRK-fusion in different brain tumours
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