<i>NTRK</i> fusions in osteosarcoma are rare and non‐functional events

Ameline, Baptiste; Saba, Karim H.; Kováč, Michal; Magnusson, Linda; Witt, Olaf; Bielack, Stefan; Nathrath, Michaela; Nord, Karolin Hansén; Baumhoer, Daniel

doi:10.1002/cjp2.158

Cited by 18 publications

(18 citation statements)

References 15 publications

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“…Novel structural variants involving gene kinases need to be confirmed at the RNA level to exclude random or non‐transcribed events. In this respect, one recent study identified NTRK fusions by DNA‐based NGS in rare osteosarcoma cases, however, these abnormalities lacked functional impact, suggesting that treatment approaches using pan‐NTRK TKIs in this setting are unlikely to benefit these patients, as these fusions likely represent randomly occurring passenger alterations 27 . Moreover, based on accumulated sequencing data, sarcomas characterized by complex genomics are less likely to harbor kinase gene fusions as driver events 28…”

Section: Discussionmentioning

confidence: 99%

Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria

Antonescu

2020

Genes Chromosomes & Cancer

109

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A recent breakthrough in the classification of soft tissue tumors (STT) has been a significant expansion in the number of neoplasms associated with NTRK and other kinase related fusions. This is important not only for diagnostic purposes, but also because it opens new avenues for targeted therapy. Indeed, recent clincal trials have shown significant benefit across multiple tumor-types, prompting approval of NTRK inhibitors for clinical use in the setting of advanced/metastatic NTRK-rearranged neoplasms. Despite these therapeutic oportunities, diagnostic challenges have transpired in recognizing these emerging new histologic subtypes of kinase fusions positive-STT prospectively. This, in part, is attributable to their wide morphologic spectrum, variable risk of malignancy, and non-specific immunoprofile. As such, recommendations for pathologic criteria and immunohistochemical testing are needed to improve classification and streamline the small subset of potential candidates for further molecular validation. This overview summarizes the key histologic features of various STT associated with NTRK and other kinase fusions, which appear to share a similar morphologic spectrum. Immunohistochemically, many of these tumors, regardless of the kinase fusion type, notably show co-expression of S100 and CD34; issues related to the utility of pan-NTRK and NTRK1 immunostaining are therefore summarized. Finally, I discuss the role of confirmatory molecular testing and how, in some instances, this may also be of prognostic value. This review is intended as a critical summary of the current literature to emphasize pathologic criteria for improving recognition of this emerging and complex group of kinase fusion associated STT. K E Y W O R D S

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Section: Discussionmentioning

confidence: 99%

Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria

Antonescu

2020

Genes Chromosomes & Cancer

109

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“…Although a lot of research is done on soft tissue tumors, little is known about the role of NTRK fusions in bone sarcomas. A very interesting study revealed three osteosarcoma samples with non-functional NTRK fusions [ 32 ]. In the first case, an NTRK2-UFD1 fusion was identified.…”

Section: Histopathology Of Sarcomas Showing Ntrk mentioning

confidence: 99%

NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects

et al. 2021

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Tropomyosin receptor kinase (TK) is encoded by the neurotrophic tyrosine receptor kinase genes (NTRK) 1, 2, and 3, whose activation plays an important role in cell cycle proliferation and survival. Fusions of one of these genes can lead to constitutive activation of TRK, which can potentially be oncogenic. NTRK fusions are commonly present in rare histologic tumor types. Among sarcomas, infantile fibrosarcoma shows NTRK fusion in more than 90% of the cases. Many other sarcoma types are also investigated for NTRK fusions. These fusions are druggable alteration of the agnostic type, meaning that all NTRK fused tumors can be treated with NTRK-inhibitors regardless of tumor type or tissue of origin. TRK-inhibitors have shown good response rates, with durable effects and limited side effects. Resistance to therapy will eventually occur in some cases, wherefore the next-generation TRK-inhibitors are introduced. The diagnosis of NTRK fused tumors, among them sarcomas, remains an issue, as many algorithms but no guidelines exist to date. Given the importance of this diagnosis, in this paper we aim to (1) analyze the histopathological features of sarcomas that correlate more often with NTRK fusions, (2) give an overview of the TRK-inhibitors and the problems that arise from resistance to the therapy, and (3) discuss the diagnostic algorithms of NTRK fused tumors with emphasis on sarcomas.

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“…So legen beispielsweise mehrere Berichte zu ALK(anaplastische Lymphomkinase)-positiven Lungenkarzinomen nahe, dass Translokationen mit verschiedenen Fusionspartnern und Bruchpunkten unterschiedliche biologische Eigenschaften aufweisen [ 68 ] und mit unterschiedlichen klinischen Therapieverläufen assoziiert [ 8 , 37 ] sein können. Bei genetisch komplexen Tumoren, nachgewiesen bei Osteosarkomen, können NTRK -Fusionen auch zu nichtfunktionalen Genprodukten führen [ 3 ].…”

Section: Ntrk -Genfusionen Als Onkogene Treiberunclassified

Diagnosis and therapy of tumors with NTRK gene fusion

et al. 2020

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ZusammenfassungNTRK-Genfusionen sind seltene genetische Alterationen, die tumorentitätenübergreifend vorkommen können. Während sie in den meisten soliden Tumoren nur sehr niederfrequent vorkommen, lassen sie sich in bestimmten Tumoren wie dem infantilen Fibrosarkom, dem kongenitalen mesoblastischen Nephrom und dem sekretorischen Mamma- oder Speicheldrüsenkarzinom jedoch häufig nachweisen. NTRK-Genfusionen bzw. TRK-Fusionsproteine gelten als starke onkogene Treiber. Bei Nachweis von NTRK-Genfusionen können TRK-Inhibitoren unabhängig von der Tumorentität eingesetzt werden. Vertreter sind Entrectinib und Larotrectinib. Bislang ist nur Larotrectinib in der Europäischen Union zugelassen. Für beide wurden Wirksamkeit und Verträglichkeit in Phase-I- und Phase-II-Studien gezeigt. Die Seltenheit der TRK-Fusionstumoren stellt diagnostische und klinische Prozesse vor große Herausforderungen: Einerseits sollen alle Patienten mit TRK-Fusionstumoren identifiziert werden, andererseits sind epidemiologische und histologische Aspekte sowie Ressourcen zu berücksichtigen. Basierend auf diesen Punkten möchten wir einen Diagnosealgorithmus für TRK-Fusionstumoren vorschlagen, außerdem stellen wir aktuelle Daten zu den TRK-Inhibitoren vor.

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NTRK fusions in osteosarcoma are rare and non‐functional events

Cited by 18 publications

References 15 publications

Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria

Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria

NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects

Diagnosis and therapy of tumors with NTRK gene fusion

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