Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Abstract

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.

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

“…In the subgroup of infant hemispheric glioma (IHG), nearly two-thirds of cases harbor molecular alterations of anaplastic lymphoma kinase ( ALK ), NTRK , ROS1 or tyrosine-protein kinase MET [ 7 , 8 ]. Adult and infant NTRK -fused gliomas are primarily located in the hemispheres with high-grade histology, whereas in older children, a more diverse anatomic distribution and low to high-grade histologic grades are found [ 9 ]. Adjuvant chemotherapy (CT) after surgery is the first approach in infants and allows delay or even avoidance of radiotherapy (RT) with a 5-year overall survival (OS) of 25.0% and 42.9% in ROS1 - and NTRK -driven tumors, respectively [ 7 , 10 , 11 ].…”

Recurrent SPECC1L–NTRK fusions in pediatric sarcoma and brain tumors

“…This fusion is not detectable by routine FISH and highlights the role of genome-wide approaches like WGS and RNA-seq, in identifying diagnostic and therapeutic targets. The SPECC1L–NTRK2 fusion has been reported recently in pediatric glioma with anaplastic features ( Torre et al 2020 ) and in pediatric mixed neuronal glial tumor ( Surrey et al 2019 ), whereas the SPECC1L–NTRK3 fusion has been seen in undifferentiated sarcomas of the uterus ( Gatalica et al 2019 ; Hodgson et al 2020 ; Rabban et al 2020 ) and in mesenchymal tumors of the gastrointestinal tract ( Atiq et al 2020 ). SPECC1L is a gene encoding a coiled-coil domain protein located on 22q11.23.…”

NTRK Fusions and TRK Inhibitors: Potential Targeted Therapies for Adult Glioblastoma

“…Zheng et al reported ARHGEF2-NTRK1 and CHTOP-NTRK1 fusion through reverse transcription-polymerase chain reaction (RT-PCR), and no similar conclusions have been reported to date (23). In 2018, Ferguson et al and Gatalica et al reported NTRK 2/3 gene fusions in adult GBM (17,26), and most recently, Torre et al and Woo et al identified several new NTRK fusions ( Table 1) (21,27). However, as molecular pathology, such as MGMT promoter methylation and EGFR mutations, was acknowledged to playing an important role in the management of adult GBM, more studies are need to clarify the status of NTRK fusions in patients with different subtype of GBM.…”

“…However, some NTRK fusions cannot be expressed into functional proteins, and the mechanisms remain unclear (11,30). NTRK fusion mutation may lead to a change of methylation status of partner genes, and GBM with NTRK fusions shown different gene methylation pattern, which is needed further researches in the future (21). Also, the relationship between the detecting frequency, variants and biological mechanisms of NTRK fusions with typical molecular pathology in adult glioma, such as IDH mutation, EGFR amplification, MGMT promoter methylation and so on, are remain unknown.…”