Expanding the spectrum of pediatric <i>NTRK</i>‐rearranged fibroblastic tumors to the central nervous system: A case report with <i>RBPMS‐NTRK3</i> fusion

Torre, Matthew; Jessop, Nicholas A.; Hornick, Jason L.; Alexandrescu, Sanda

doi:10.1111/neup.12513

Cited by 18 publications

(15 citation statements)

References 27 publications

(44 reference statements)

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“…RBPMS, an RNA-binding protein, and MET, a proto-oncogene receptor tyrosine kinase, have been identified as fusion partners in a variety of cancers with other genes and as gene fusion partners in a patient with cholangiocarcinoma [ 37 ]. Although MET fusions are uncommon drivers of sarcoma [ 38 ], a TFG-MET fusion has been reported in a patient with an infantile spindle cell sarcoma with neural features [ 37 , 39 , 40 ]. The interchromosomal in-frame fusion of RBPMS (ENST00000320203, exon 5) to MET (ENST00000318493, exon 15) juxtaposes the RNA recognition motif of RBPMS to the MET tyrosine kinase catalytic domain (Fig.…”

Section: Resultsmentioning

confidence: 99%

Discovery of clinically relevant fusions in pediatric cancer

et al. 2021

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Background Pediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis. Sensitive and specific detection of gene fusions through the analysis of next-generation-based RNA sequencing (RNA-Seq) data is computationally challenging and may be confounded by low tumor cellularity or underlying genomic complexity. Furthermore, numerous computational tools are available to identify fusions from supporting RNA-Seq reads, yet each algorithm demonstrates unique variability in sensitivity and precision, and no clearly superior approach currently exists. To overcome these challenges, we have developed an ensemble fusion calling approach to increase the accuracy of identifying fusions. Results Our Ensemble Fusion (EnFusion) approach utilizes seven fusion calling algorithms: Arriba, CICERO, FusionMap, FusionCatcher, JAFFA, MapSplice, and STAR-Fusion, which are packaged as a fully automated pipeline using Docker and Amazon Web Services (AWS) serverless technology. This method uses paired end RNA-Seq sequence reads as input, and the output from each algorithm is examined to identify fusions detected by a consensus of at least three algorithms. These consensus fusion results are filtered by comparison to an internal database to remove likely artifactual fusions occurring at high frequencies in our internal cohort, while a “known fusion list” prevents failure to report known pathogenic events. We have employed the EnFusion pipeline on RNA-Seq data from 229 patients with pediatric cancer or blood disorders studied under an IRB-approved protocol. The samples consist of 138 central nervous system tumors, 73 solid tumors, and 18 hematologic malignancies or disorders. The combination of an ensemble fusion-calling pipeline and a knowledge-based filtering strategy identified 67 clinically relevant fusions among our cohort (diagnostic yield of 29.3%), including RBPMS-MET, BCAN-NTRK1, and TRIM22-BRAF fusions. Following clinical confirmation and reporting in the patient’s medical record, both known and novel fusions provided medically meaningful information. Conclusions The EnFusion pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods. Furthermore, this method accurately identifies driver fusions in pediatric cancer, providing clinical impact by contributing evidence to diagnosis and, when appropriate, indicating targeted therapies.

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Section: Resultsmentioning

confidence: 99%

Discovery of clinically relevant fusions in pediatric cancer

et al. 2021

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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 , 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 ].…”

Section: Discussionmentioning

confidence: 99%

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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“…There is a single report of a TFG-MET fusion in an unusual S100-positive infantile spindle cell sarcoma ( Flucke et al 2017 ). In terms of RBPMS involvement, there are two prior reports of RBPMS-NTRK3 fusion positive sarcomas: an adult with a fibrosarcoma-like uterine sarcoma ( Chiang et al 2018 ) and a 20-mo-old with a fibroblastic central nervous system (CNS) tumor ( Torre et al 2018 ). Additionally, RBPMS-NRG1 fusions have been described in adult lung adenocarcinoma and renal cell carcinoma ( Jonna et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Infantile fibrosarcoma–like tumor driven by novel RBPMS-MET fusion consolidated with cabozantinib

Gupta

Belsky

Schieffer

et al. 2020

Cold Spring Harb Mol Case Stud

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Infantile fibrosarcoma (IFS) is nearly universally driven by gene fusions involving the NTRK family. ETV6-NTRK3 fusions account for ∼85% of alterations; the remainder are attributed to NTRK-variant fusions. Rarely, other genomic aberrations have been described in association with tumors identified as IFS or IFS-like. We describe the utility of genomic characterization of an IFS-like tumor. We also describe the successful treatment combination of VAC (vincristine, actinomycin, cyclophosphamide) with tyrosine kinase inhibitor (TKI) maintenance in this entity. This patient presented at birth with a right facial mass, enlarging at 1 mo to 4.9 × 4.5 × 6.3 cm. Biopsy demonstrated hypercellular fascicles of spindle cells with patchy positivity for smooth muscle actin (SMA) and negativity for S100, desmin, myogenin, and MyoD1. Targeted RNA sequencing identified a novel RBPMS-MET fusion with confirmed absence of ETV6-NTRK3, and the patient was diagnosed with an IFS-like tumor. A positron emission tomography (PET) scan was negative for metastatic disease. VAC was given for a duration of 10 mo. Resection at 13 mo of age demonstrated positive margins. Cabozantinib, a MET-targeting TKI, was initiated. The patient tolerated cabozantinib well and has no evidence of disease at 24 mo of age. We describe a novel RBPMS-MET driver fusion in association with a locally aggressive IFS-like tumor. MET functions as an oncogene and, when associated with the RNA binding protein RBPMS, forms an in-frame fusion product that retains the MET kinase domain. This fusion is associated with aberrant cell signaling pathway expression and subsequent malignancy. We describe treatment with cabozantinib in a patient with an IFS-like neoplasm.

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Expanding the spectrum of pediatric NTRK‐rearranged fibroblastic tumors to the central nervous system: A case report with RBPMS‐NTRK3 fusion

Cited by 18 publications

References 27 publications

Discovery of clinically relevant fusions in pediatric cancer

Discovery of clinically relevant fusions in pediatric cancer

Molecular and clinicopathologic features of gliomas harboring NTRK fusions

Infantile fibrosarcoma–like tumor driven by novel RBPMS-MET fusion consolidated with cabozantinib

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