The Evaluation of Neurotrophic Receptor Tyrosine Kinase (NTRK) Alterations in Neuroblastomas.
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BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor among pediatric cancers and accounts for approximately 15% of childhood cancer-related deaths. Neurotrophic receptor tyrosine kinases (NTRKs) are genes that play critical roles in the development and function of the nervous system. Therefore, elucidating the role of NTRKs in NB is important for both understanding basic biological mechanisms and developing novel therapeutic approaches. Specifically, NTRK fusions are being investigated as potential biomarkers and therapeutic targets for targeted therapy strategies. The tumor-agnostic TRK inhibitors larotrectinib and entrectinib are used to treat advanced or metastatic solid tumors with NTRK gene fusions. Accordingly, this study aimed to investigate the clinical significance of NTRK1, NTRK2, and NTRK3 point mutations, gene fusions, and protein expression, and to assess the effectiveness of these in guiding targeted therapy decisions in NB. METHODS: This study investigated pan-TRK expression, point mutations, and fusions in the NTRK1, NTRK2, and NTRK3 genes using next-generation sequencing (NGS) on paraffin-embedded blocks from 173 patients diagnosed with NB. Findings were analyzed in SPSS 29.0 using clinical data, MYCN amplification, and 11q deletion status, with Pearson correlation analysis applied at the p < 0.05 significance level. RESULTS: Immunohistochemistry (IHC) for NTRK revealed that 67.9% of cases were NTRK-positive. NGS analysis identified NTRK1 missense point mutations in 20 cases, NTRK2 in 9 cases, and NTRK3 in 9 cases. In addition, 5 fusions were detected in 4 of the 103 patients who underwent fusion analysis. CONCLUSIONS: Owing to the presence of neural tissue, NTRKs are highly positive in IHC, making these genes unsuitable as biomarkers for assessing NTRK inhibitor sensitivity and resistance, which are tissue-agnostic drugs. The observed low fusion rate is consistent with the literature, and the significance of the numerous point mutations identified as agnostic markers warrants further investigation. NTRK expression, fusion, and point mutations were not associated with clinical parameters or survival.