Sustained Response to the Mitogen-Activated Extracellular Kinase Inhibitor Trametinib in a Spindle Cell Sarcoma Harboring a QKI-RAF1 Gene Fusion

Panet, François; Jung, Sungmi; Alcindor, Thierry

doi:10.1200/po.21.00303

Cited by 4 publications

(5 citation statements)

References 15 publications

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“…In line with a previous case report [12], our data establish a driver role of aberrantly upregulated RAF1 function in this still poorly characterized subtype of pediatric spindle cell tumors. Due to its 14-3-3-independent dimerization, the CLIP1::RAF1 protein functions as a constitutively activated kinase, whose catalytic upregulation can be downmodulated by MEKi treatment, in line with previous observations [42].…”

Section: Discussionsupporting

confidence: 89%

RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma‐like mesenchymal tumors

Motta,

Barresi,

Pizzi

et al. 2024

The Journal of Pathology

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Infantile fibrosarcomas (IFS) and congenital mesoblastic nephroma (CMN) are rare myofibroblastic tumors of infancy and early childhood commonly harboring the ETV6::NTRK3 gene fusion. IFS/CMN are considered as tumors with an ‘intermediate prognosis’ as they are locally aggressive, but rarely metastasize, and generally have a favorable outcome. A fraction of IFS/CMN‐related neoplasms are negative for the ETV6::NTRK3 gene rearrangement and are characterized by other chimeric proteins promoting MAPK signaling upregulation. In a large proportion of these tumors, which are classified as IFS‐like mesenchymal neoplasms, the contributing molecular events remain to be identified. Here, we report three distinct rearrangements involving RAF1 among eight ETV6::NTRK3 gene fusion‐negative tumors with an original histological diagnosis of IFS/CMN. The three fusion proteins retain the entire catalytic domain of the kinase. Two chimeric products, GOLGA4::RAF1 and LRRFIP2::RAF1, had previously been reported as driver events in different cancers, whereas the third, CLIP1::RAF1, represents a novel fusion protein. We demonstrate that CLIP1::RAF1 acts as a bona fide oncoprotein promoting cell proliferation and migration through constitutive upregulation of MAPK signaling. We show that the CLIP1::RAF1 hyperactive behavior does not require RAS activation and is mediated by constitutive 14‐3‐3 protein‐independent dimerization of the chimeric protein. As previously reported for the ETV6::NTRK3 fusion protein, CLIP1::RAF1 similarly upregulates PI3K‐AKT signaling. Our findings document that RAF1 gene rearrangements represent a recurrent event in ETV6::NTRK3‐negative IFS/CMN and provide a rationale for the use of inhibitors directed to suppress MAPK and PI3K‐AKT signaling in these cancers. © 2024 The Pathological Society of Great Britain and Ireland.

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Section: Discussionsupporting

confidence: 89%

RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma‐like mesenchymal tumors

Motta,

Barresi,

Pizzi

et al. 2024

The Journal of Pathology

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“…[14][15][16] The detection of these gene fusions is of great significance from not only diagnostic perspectives, but also therapeutic standpoints, as a significant minority of cases may behave aggressively, and therefore may benefit from treatment with selective kinase inhibitors. 6,10,[17][18][19][20][21][22][23] The RET proto-oncogene, located at 10q11.21, encodes a transmembrane receptor and member of the tyrosine protein kinase family. Activation of RET via cytogenetic rearrangements, in-frame deletions, or point mutations can lead to activation of the RAS-RAF-MAPK signalling pathway, promoting cell survival and proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…8,12,13,23,[26][27][28][29][30][31] Prior reports have described mesenchymal neoplasms harbouring RET rearrangements primarily in the soft tissues of infants and children, but very rarely in internal organs or in adult patients. 12,13,21,29,31 They have a similar phenotypic spectrum to the NTRK-fusion tumours, with at least four different growth patterns, including lipofibromatosis-like neural tumour (LNF-NT)-like, fibrosarcoma-like, low-grade malignant peripheral nerve sheath tumour (LG-MPNST)-like, and high-grade malignant peripheral nerve sheath tumour (HG-MPNST)like. 12,13 Immunohistochemically, these tumours either show variable expression of S100 protein and CD34, or display a nonspecific immunoprofile.…”

Section: Introductionmentioning

confidence: 99%

“…These neoplasms are often associated with monomorphic spindle‐cell morphology, with a wide spectrum of growth patterns and nonspecific immunohistochemical profiles, raising significant diagnostic challenges 14–16 . The detection of these gene fusions is of great significance from not only diagnostic perspectives, but also therapeutic standpoints, as a significant minority of cases may behave aggressively, and therefore may benefit from treatment with selective kinase inhibitors 6,10, 17–23 …”

Section: Introductionmentioning

confidence: 99%

“…In mesenchymal neoplasms, RET rearrangements have only rarely been documented, with multiple nosological terms applied 8,12,13,23,26–31 . Prior reports have described mesenchymal neoplasms harbouring RET rearrangements primarily in the soft tissues of infants and children, but very rarely in internal organs or in adult patients 12,13,21,29,31 . They have a similar phenotypic spectrum to the NTRK‐ fusion tumours, with at least four different growth patterns, including lipofibromatosis‐like neural tumour (LNF‐NT)‐like, fibrosarcoma‐like, low‐grade malignant peripheral nerve sheath tumour (LG‐MPNST)‐like, and high‐grade malignant peripheral nerve sheath tumour (HG‐MPNST)‐like 12,13 .…”

Section: Introductionmentioning

confidence: 99%

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Recurrent RET fusions in fibrosarcoma‐like neoplasms in adult viscera: expanding the clinicopathological and genetic spectrum

Zhao

Yin

et al. 2022

Histopathology

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Aims: RET-fused mesenchymal neoplasms mostly affect the soft tissue of paediatric patients. Given their responsiveness to selective RET inhibitors, it remains critical to identify those extraordinary cases occurring in the visceral organs of adults. In this study, we report three RET-rearranged spindle-cell tumours occurring in the visceral organs of adults. Methods and Results: Clinicopathological features were assessed and partner agnostic targeted nextgeneration sequencing on clinically validated platforms were performed. The patients were 18, 53, and 55 years old and included one male and two females. The tumours were located in the kidney (case 1), small intestine (case 2), and ureter (case 3), with maximum diameters of 14, 5, and 1 cm, respectively. Histologically, all tumours displayed a morphological spectrum typical of fibrosarcoma, including moderately to highly cellular, nonpleomorphic, ovoid to spindle-shaped cells arranged in long fascicles or haphazardly within collagenised to myxohyaline stroma. Foci of irregular alveolar oedema-like structures and areas with microcystic and reticular arrangements were identified in the renal tumour. Staghorn-type vessels and foci of band-like stromal hyalinisation were observed in the small intestine tumour. Cases 1 and 2 were high-grade and pursed a highly aggressive clinical course, while case 3 was of intermediate grade with no tumour recurrence or metastasis 14 years after surgery. All three tumours expressed CD34, which was coexpressed with S100 protein in cases 2 and 3. Molecular genetic testing revealed PRKAR1A::RET, KIF5B::RET, and SPECC1L::RET inframe gene fusions. Conclusion: Our study expands the clinicopathological and genetic spectrum of mesenchymal neoplasms associated with RET fusions.

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Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors With NTRK, BRAF, RAF1, or RET Fusions

Kojima¹,

Mori²,

Motoi³

et al. 2023

Modern Pathology

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Sustained Response to the Mitogen-Activated Extracellular Kinase Inhibitor Trametinib in a Spindle Cell Sarcoma Harboring a QKI-RAF1 Gene Fusion

Cited by 4 publications

References 15 publications

RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma‐like mesenchymal tumors

RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma‐like mesenchymal tumors

Recurrent RET fusions in fibrosarcoma‐like neoplasms in adult viscera: expanding the clinicopathological and genetic spectrum

Frequent CD30 Expression in an Emerging Group of Mesenchymal Tumors With NTRK, BRAF, RAF1, or RET Fusions

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