Novel <i>TLE4‐NTRK2</i> fusion in a ganglioglioma identified by array‐CGH and confirmed by NGS: Potential for a gene targeted therapy

Prabhakaran, Nitya; Guzmán, Miguel A.; Navalkele, Pournima; Chow-Maneval, Edna; Batanian, Jacqueline R.

doi:10.1111/neup.12458

Cited by 18 publications

(10 citation statements)

References 20 publications

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“…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,…”

Section: Discussionmentioning

confidence: 73%

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Torre

Vasudevaraja

Serrano

et al. 2020

acta neuropathol commun

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Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low-to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.

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Section: Discussionmentioning

confidence: 73%

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Torre

Vasudevaraja

Serrano

et al. 2020

acta neuropathol commun

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“…Additionally, a single case of a lowgrade diffuse glioma has been reported with an NTRK2 gene fusion (Table 1) [8]. NTRK2 fusion partners in nonpilocytic astrocytoma low-grade gliomas include QKI, SLMAP, TLE4, NAV1, and BCR [8][9][10][11]. Here, we describe a patient where a novel PML-NTRK2 gene fusion was identified in an adult sporadic pilocytic astrocytoma.…”

Section: Introductionmentioning

confidence: 83%

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

Pattwell

Konnick

Liu

et al. 2020

Case Reports in Pathology

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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.

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“…NTRK rearrangements have been investigated and discovered with a notable frequency in mixed glioneuronal tumors, a rare group of pediatric epileptogenic CNS neoplasms. Once again, although rare, NTRK (particularly NTRK1) fusions have been identified in both low-grade and high-grade glioneuronal tumors, ranging from ganglioglioma to diffuse leptomeningeal glioneuronal tumors [124][125][126][127].…”

Section: Ntrk Fusions In Pediatric Cns Tumorsmentioning

confidence: 99%

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

Gambella

Senetta

Collemi

et al. 2020

IJMS

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The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.

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Novel TLE4‐NTRK2 fusion in a ganglioglioma identified by array‐CGH and confirmed by NGS: Potential for a gene targeted therapy

Cited by 18 publications

References 20 publications

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

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

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

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