Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2) Alterations in Low-Grade Gliomas: Report of a Novel Gene Fusion Partner in a Pilocytic Astrocytoma and Review of the Literature

Abstract

Pilocytic astrocytoma is a low-grade glial neoplasm of the central nervous system (CNS) that tends to occur in the pediatric population and less commonly presents in adults. Hereditary pilocytic astrocytoma is often associated with germline genetic alterations in the tumor suppressor NF1, the gene responsible for the syndrome neurofibromatosis type 1. Sporadic pilocytic astrocytoma frequently harbors somatic alterations in BRAF, with rare pilocytic astrocytomas containing alterations in FGFR1 and NTRK2. NTRK2 encodes for the protein tropomyosin receptor kinase B (TrkB), which is a neurotrophin receptor with high affinity for Brain-Derived Neurotrophic Factor (BDNF), and plays a role in several physiological functions of neurons, including cell survival and differentiation. In this report, we describe a novel PML-NTRK2 gene fusion occurring in an adult sporadic pilocytic astrocytoma and review the biology and implications of specific NTRK2 mutations occurring in CNS neoplasms.

Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib

“…Previously reported NTRK2 fusions in low-grade glioma include AFAP1-NTRK2 , 24 NACC2-NTRK2, QKI-NTRK2, 16 KANK1-NTRK2 , 39 BRC-NTRK2 40 and PML-NTRK2 . 35 Reviewing the literature, we found GKAP1-NTRK2 fusions listed in two recent screening studies; one in a pLGG tumor harboring a exon 9–15 fusion junction, 41 and another in an adult glioblastoma multiforme patient with the same exon 10–16 fusion junction as the one detected in this study. 42 However, no details about the disease course for these patients were provided.…”

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

“…The diverse histology of NTRK-fused gliomas overlaps with entities such as DIGG, GG, PXA, PA (including anaplastic), DA grades 2 and 3, and GBM in our study. In keeping with the wide spectrum of NTRK-fused CNS tumor histology, NTRK rearrangements have been previously reported in GBM [9,18,19,21,28,34,38,39,41,43,44,52,53,56], gliosarcoma [21], AA [9,18,21,52], diffuse midline glioma / DIPG [9,52], HGG [9,22,34,57], glioneuronal tumor (including high grade) [1,16,29], pilocytic astrocytoma (PA) (including anaplastic) [9,18,21,25,35], low grade astrocytroma with features of PA [26], PXA [55], GG [1,9,36,37], DIGG [6,9], LGG [18,34,44,50,53], glioma, not otherwise specified [9,…”

“…The diverse histology of NTRK -fused gliomas overlaps with entities such as DIGG, GG, PXA, PA (including anaplastic), DA grades 2 and 3, and GBM in our study. In keeping with the wide spectrum of NTRK -fused CNS tumor histology, NTRK rearrangements have been previously reported in GBM [ 9 , 18 , 19 , 21 , 28 , 34 , 38 , 39 , 41 , 43 , 44 , 52 , 53 , 56 ], gliosarcoma [ 21 ], AA [ 9 , 18 , 21 , 52 ], diffuse midline glioma / DIPG [ 9 , 52 ], HGG [ 9 , 22 , 34 , 57 ], glioneuronal tumor (including high grade) [ 1 , 16 , 29 ], pilocytic astrocytoma (PA) (including anaplastic) [ 9 , 18 , 21 , 25 , 35 ], low grade astrocytroma with features of PA [ 26 ], PXA [ 55 ], GG [ 1 , 9 , 36 , 37 ], DIGG [ 6 , 9 ], LGG [ 18 , 34 , 44 , 50 , 53 ], glioma, not otherwise specified [ 9 , 18 ], neuroepithelial neoplasm [ 43 ], CNS fibroblastic tumor [ 47 ], primitive neuroectodermal tumor (PNET) [ 12 ], CNS embryonal tumor [ 14 ], and tumors with oligodendroglial or oligoastrocytic-like histology [ 12 , 21 , 29 , 37 , 55 ].…”

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways

“…T1 isoform is still able to be generated in its full form from the reciprocal cross, if the fusion breakpoint is downstream of the unique TrkB.T1 exon. The possibility exists that in addition to Gene ratio creating constitutively active kinases through various fusion partners, these fusions may, in some cases, also be inherently selecting for the production of TrkB.T1 55 . Similarly, analysis of mouse tumorspheres generated with NTRK2 fusions 56 shows that they express TrkB.T1 as their most highly expressed isoform ( Supplementary Fig.…”