Pediatric NTRK-rearranged gliomas: A clinicopathological and molecular analysis of six cases.

AIMS Neurotrophic tyrosine receptor kinase (NTRK) gene fusions, although present in fewer than 2 % of gliomas, are recognized oncogenic drivers. With the approval of NTRK-targeted therapies, increasing attention has focused on these tumors, as targeted treatments may substantially enhance outcomes. This study aimed to characterize the pathological features and molecular diversity of pediatric NTRK-rearranged gliomas to inform targeted therapeutic strategies.

METHODS AND RESULTS We analyzed six pediatric gliomas harboring NTRK fusions, identified through next-generation DNA sequencing (n = 5) and fluorescence in situ hybridization (n = 6). All tumors were supratentorial, involving the cerebral hemispheres (n = 3), thalamus (n = 2), and pineal region (n = 1). All infantile cases (n = 3) demonstrated high-grade histology and predominantly involved NTRK1, with one NTRK3 fusion. The three low-grade gliomas included two with NTRK1 and one with NTRK2 rearrangement. Dual gene fusions were identified in one case with intrachromosomal BCAN exon 14-NTRK1 exon 11 and NTRK1 exon 8-ARHGEF11 exon 2 rearrangements. One case harbored triple gene fusions, including interchromosomal ETV6-NTRK3 and PHYH-ETV6 fusions and an intrachromosomal NTRK3 rearrangement. Additional genetic alterations were detected in three cases, involving CDKN2A/B, TP53, ROS1, ABL1, MSH2, ARID4A, and CHEK1. DNA methylation profiling showed no collective methylation class and low-confidence matches to established methylation families.

CONCLUSION This study expands the clinicopathological and molecular spectrum of pediatric NTRK-rearranged gliomas, including rare entities and complex fusion patterns, and supports routine NTRK testing in pediatric gliomas irrespective of histological grade.