<i>ETV6</i>–<i>NTRK3</i> in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study

Vokuhl, Christian; Nourkami-Tutdibi, Nasenien; Furtwängler, Rhoikos; Gessler, Manfred; Graf, Norbert; Leuschner, Ivo

doi:10.1002/pbc.26925

Cited by 46 publications

(41 citation statements)

References 22 publications

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“…The use of either NTRK3 FISH or next‐generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients. In a report of the International Society of Pediatric Oncology/Gesellschaft fur Padiatrische Onkologie und Hamatologie, 58% of cases with cellular variant CMN had the ETV6 – NTRK3 fusion, and none were detected in classical type …”

Section: Discussionmentioning

confidence: 99%

“…In a report of the International Society of Pediatric Oncology/Gesellschaft fur Padiatrische Onkologie und Hamatologie, 58% of cases with cellular variant CMN had the ETV6-NTRK3 fusion, and none were detected in classical type. 5 Recurrences are rare and have been described in approximately 4% of the cases. 12 Relapses more commonly occur locally, but distant metastasis in the lung and liver have been reported; bone metastases are extremely rare and account for 5.5% of reported cases with metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with cellular CMN usually have a good prognosis following nephrectomy, with event‐free and overall survival greater than 94%, however, there are rare case reports of patients with local failure and/or metastatic disease . Patients diagnosed with metastatic disease are usually treated with vincristine/actinomycin‐D or doxorubicin/vincristine/cyclophosphamide.…”

Section: Introductionmentioning

confidence: 99%

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Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma

Halalsheh

McCarville

Neel

et al. 2018

Pediatric Blood & Cancer

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Mesoblastic nephroma is the most frequent renal tumor in newborns and young infants, and the cellular type is characterized by an ETV6-NTRK fusion, which constitutively activates the tropomyosin-related kinase (TRK) signaling pathway. Larotrectinib is a highly selective TRK inhibitor with activity in adult and pediatric patients who have TRK fusions. We present a rare case of a patient with mesoblastic nephroma metastatic to bone who had a dramatic response to larotrectinib.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma

Halalsheh

McCarville

Neel

et al. 2018

Pediatric Blood & Cancer

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“…9 Compared to translocation-negative variants of congenital mesoblastic nephroma with classic or mixed histology, the cellular variant with ETV6-NTRK3 fusion carries a far better prognosis in terms of relapse free and overall survival. 10 Some of the genetic alterations found in pediatric IFS-like sarcomas have also been described in subsets of CMN, including EML4-NTRK3, 4 LMNA-NTRK1, and BRAF intragenic deletions, 7 providing further evidence that IFS and CMN are histogenetically related entities.…”

Section: Cellular Mesoblastic Nephroma-shared Genetics With Ifsmentioning

confidence: 96%

New advances in the molecular classification of pediatric mesenchymal tumors

Suurmeijer

Kao

Antonescu

2018

Genes Chromosomes & Cancer

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Pediatric soft tissue tumors are relatively rare and show significant overlap in morphology and immunoprofile, often posing diagnostic and management challenges. Thus, their classification remains often subjective or lumped under "unclassified categories," as a number of lesions lack objective and reproducible criteria in diagnosis. Although in a subset of cases immunohistochemistry has been proved useful to identify a specific line of differentiation, most tumors lack a readily defined histogenesis, being characterized by a rather non-specific immunoprofile. Furthermore, tumors with an ambiguous diagnosis are difficult to grade and their risk of malignancy or clinical management remains uncertain. Advances in molecular genetics, including the more wide application of next generation sequencing in routine clinical practice, have improved diagnosis and refined classification based on objective molecular markers. Importantly, some soft tissue tumors in children are characterized by recurrent gene fusions involving either growth factors (eg, PDGFB) or protein kinases (eg, ALK, ROS, NTRK, BRAF), which have paved the way for new targeted treatments that block the respective upregulated downstream pathways. However, the majority of gene fusions or mutations detected in soft tissue tumors result in an abnormal function of transcription factors or chromatin remodeling. The present review focuses on the latest genetic discoveries in the spectrum of both benign and malignant pediatric soft tissue neoplasia. These genetic abnormalities promise to provide relevant insight for their proper classification, prognosis, and treatment. The entities discussed herein are grouped either based on their shared genetic mechanism or based on their presumed line of differentiation.

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“…In addition, an LMNA-NTRK1 fusion in a congenital infantile fibrosarcoma, [62] and LMNA-NTRK1 and TMP3-NTRK1 fusions in ETV6-NTRK3 fusion-negative congenital/infantile soft tissue lesions with similar morphological features to congenital infantile fibrosarcoma have been identified [63]. Similarly, most cases of the cellular subtype of the rare pediatric renal tumor, congenital mesoblastic nephroma, have ETV6-NTRK3 fusions [51,52], although again, the EML4-NTRK3 fusion may also be found [49]. The identification of variant NTRK gene fusions in these particular tumor types is of significance in relation to the screening strategies that might be used in these indications to select patients for TRK inhibitor therapy.…”

Section: Ntrk Gene Fusionsmentioning

confidence: 98%

TRK Inhibition: A New Tumor-Agnostic Treatment Strategy

Kummar

Lassen

2018

Targ Oncol

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Oncogenic somatic chromosomal rearrangements involving the NTRK1, NTRK2 or NTRK3 genes (NTRK gene fusions) occur in up to 1% of all solid tumors, and have been reported across a wide range of tumor types. The fusion proteins encoded by such rearranged sequences have constitutively activated TRK tyrosine kinase domains, providing novel therapeutic anticancer targets. The potential clinical effectiveness of TRK inhibition in patients with tumors harboring NTRK gene fusions is being assessed in phase I and II trials of TRK inhibitors, such as larotrectinib and entrectinib. Clinical trial results have demonstrated that larotrectinib is generally well tolerated and has shown high response rates that are durable across tumor types. These data validate NTRK gene fusions as actionable genomic alterations. In this review, we present the clinical data, discuss the different approaches that might be used to routinely screen tumors to indicate the presence of NTRK gene fusions, explore the issue of acquired resistance to TRK inhibition, and reflect on the wider regulatory considerations for tumor site agnostic TRK inhibitor drug development.

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ETV6–NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study

Abstract: The majority of cellular MNs harbor the ETV6-NTKR3 gene fusion, whereas all classic- and mixed-type MNs were translocation negative. Within the cellular subgroup, patients having translocation-positive tumors had a significantly superior RFS.

Cited by 46 publications

References 22 publications

Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma

Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma

New advances in the molecular classification of pediatric mesenchymal tumors

TRK Inhibition: A New Tumor-Agnostic Treatment Strategy

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