NTRK rearrangements in a subset of NF1-related malignant peripheral nerve sheath tumors as novel actionable target

Hiemcke-Jiwa, Laura S.; Meister, Michael T.; Martin, Enrico; Dierselhuis, Miranda P.; Haveman, Lianne M.; R, Meijers; Tops, Bastiaan B.J.; Wesseling, Pieter; Diest, Paul J. van; Gorp, Joost M. van; Hehir-Kwa, Jayne Y.; Belzen, Ianthe A. E. M. van; Bonenkamp, J J; Noesel, Max M. van; Flucke, Uta; Kester, Lennart

doi:10.1007/s00401-022-02515-3

Cited by 5 publications

(6 citation statements)

References 10 publications

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“…[33][34][35][36] Although neurofibromatosis (NF1)-association is common in classic MPNST, rare cases of high-grade MPNST-like kinase fusion tumors have been reported recently to occur in the setting of NF1. 16 However, in contrast to BTKF, classic MPNST often shows loss of the H3K27me3 expression, 37 as shown in the unique case #7 included in this series, which represents a primary MPNST of bone and harboring UPF2::NTRK3 fusion in addition to TP53 H179L mutation, loss of CDKN2A/B, and loss of EED. The patient did not have clinical history or stigmata of NF1.…”

Section: Clinical Outcomementioning

confidence: 79%

“…Finally, a subgroup of FS‐like or MPNST‐like tumors represent higher grade lesions, which have a predilection for NTRK3 gene fusions 5 . On very rare occasions, these tumors are associated with neurofibromatosis (NF1) 16 . Clinical follow‐up, albeit limited, has emphasized that tumors with a high‐grade malignant phenotype have the propensity for distant spread and follow an aggressive clinical course 4,5 …”

Section: Discussionmentioning

confidence: 99%

“…Other extremely rare skeletal presentations of soft tissue tumors, such as the monophasic variant of synovial sarcoma and classic MPNST, may be confused with high‐grade variants of FS‐like or MPNST‐like BTKF 33–36 . Although neurofibromatosis (NF1)‐association is common in classic MPNST, rare cases of high‐grade MPNST‐like kinase fusion tumors have been reported recently to occur in the setting of NF1 16 . However, in contrast to BTKF, classic MPNST often shows loss of the H3K27me3 expression, 37 as shown in the unique case #7 included in this series, which represents a primary MPNST of bone and harboring UPF2::NTRK3 fusion in addition to TP53 H179L mutation, loss of CDKN2A/B , and loss of EED .…”

Section: Discussionmentioning

confidence: 99%

“…5 On very rare occasions, these tumors are associated with neurofibromatosis (NF1). 16 Clinical follow-up, albeit limited, has emphasized that tumors with a high-grade malignant phenotype have the propensity for distant spread and follow an aggressive clinical course. 4,5 Some of the detected NTRK3, RET, and BRAF kinase fusions in this series were novel or uncommon.…”

Section: Pan-trk Immunostainingmentioning

confidence: 99%

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Kinase fusion positive intra‐osseous spindle cell tumors: A series of eight cases with review of the literature

Suurmeijer,

Xu,

Torrence

et al. 2023

Genes Chromosomes & Cancer

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Mesenchymal spindle cell tumors with kinase fusions, often presenting in superficial or deep soft tissue locations, may rarely occur in bone. Herein, we describe the clinicopathologic and molecular data of eight bone tumors characterized by various kinase fusions from our files and incorporate the findings with the previously reported seven cases, mainly as single case reports. In the current series all but one of the patients were young children or teenagers, with an age range from newborn to 59 years (mean 19 years). Most tumors (n = 5) presented in the head and neck area (skull base, mastoid, maxilla, and mandible), and remaining three in the tibia, pelvic bone, and chest wall. The fusions included NTRK1 (n = 3), RET (n = 2), NTRK3 (n = 2), and BRAF (n = 1). In the combined series (n = 15), most tumors (73%) occurred in children and young adults (<30 years) and showed a predilection for jaw and skull bones (40%), followed by long and small tubular bones (33%). The fusions spanned a large spectrum of kinase genes, including in descending order NTRK3 (n = 6), NTRK1 (n = 4), RET (n = 2), BRAF (n = 2), and RAF1 (n = 1). All fusions confirmed by targeted RNA sequencing were in‐frame and retained the kinase domain within the fusion oncoprotein. Similar to the soft tissue counterparts, most NTRK3‐positive bone tumors in this series showed high‐grade morphology (5/6), whereas the majority of NTRK1 tumors were low‐grade (3/4). Notably, all four tumors presenting in the elderly were high‐grade spindle cell sarcomas, with adult fibrosarcoma (FS)‐like, malignant peripheral nerve sheath tumor (MPNST)‐like and MPNST phenotypes. Overall, 10 tumors had high‐grade morphology, ranging from infantile and adult‐types FS, MPNST‐like, and MPNST, whereas five showed benign/low‐grade histology (MPNST‐like and myxoma‐like). Immunohistochemically (IHC), S100 and CD34 positivity was noted in 57% and 50%, respectively, while co‐expression of S100 and CD34 in 43% of cases. One‐third of tumors (4 high grade and the myxoma‐like) were negative for both S100 and CD34. IHC for Pan‐TRK was positive in all eight NTRK‐fusion positive tumors tested and negative in two tumors with other kinase fusions. Clinical follow‐up was too limited to allow general conclusions.

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Section: Clinical Outcomementioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pan-trk Immunostainingmentioning

confidence: 99%

See 2 more Smart Citations

Kinase fusion positive intra‐osseous spindle cell tumors: A series of eight cases with review of the literature

Suurmeijer,

Xu,

Torrence

et al. 2023

Genes Chromosomes & Cancer

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“…For instance, LMNA‐NTRK1 has been reported in Lipofibromatosis‐Like Neural Tumors, which highly resemble low‐grade MPNSTs [ 79 , 80 ]. A case report study detected this gene fusion within a subset of NF1‐related MPNSTs [ 81 ]; however, the histological and molecular characterization of these tumors was scarce. Finally, according to genomic characteristics, tumor SP‐06 is clearly distinct from classic MPNSTs ( NF2 inactivation, NRAS oncogenic mutation, and truncating mutation in SMARCA4 ).…”

Section: Discussionmentioning

confidence: 99%

Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

Creus‐Bachiller,

Fernández‐Rodríguez,

Magallón‐Lorenz

et al. 2023

Molecular Oncology

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient‐derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro–in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another an Neurotrophic tyrosine receptor kinase (NTRK)‐rearranged spindle cell neoplasm, and, finally, an unclassifiable tumor bearing Neurofibromin‐2 (NF2) inactivation, an Neuroblastoma RAS Viral Oncogene Homolog (NRAS) oncogenic mutation and a SWI/SNF‐related Matrix associated Actin‐dependent Regulator of Chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted on treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.

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RABEP1::RET in a Malignant Peripheral Nerve Sheath Tumor of a Pediatric Patient With Neurofibromatosis Type 1

Hiemcke-Jiwa,

van Noesel,

Martin

et al. 2024

Int J Surg Pathol

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NTRK rearrangements in a subset of NF1-related malignant peripheral nerve sheath tumors as novel actionable target

Cited by 5 publications

References 10 publications

Kinase fusion positive intra‐osseous spindle cell tumors: A series of eight cases with review of the literature

Kinase fusion positive intra‐osseous spindle cell tumors: A series of eight cases with review of the literature

Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

RABEP1::RET in a Malignant Peripheral Nerve Sheath Tumor of a Pediatric Patient With Neurofibromatosis Type 1

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