دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma-like mesenchymal tumors.
المؤلفون: Motta M; Molecular Genetics and Functional Genomics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Barresi S; Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Pizzi S; Molecular Genetics and Functional Genomics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Bifano D; Pathology Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy., Lopez Marti J; Department of Pathology, Hospital Nacional de Pediatria Juan P. Garrahan, Buenos Aires, Argentina., Garrido-Pontnou M; Department of Pathology, Vall d'Hebron Hospital Universitari, Barcelona, Spain., Flex E; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy., Bruselles A; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy., Giovannoni I; Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Rotundo G; Molecular Genetics and Functional Genomics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Fragale A; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy., Tirelli V; Core Facilities, Istituto Superiore di Sanità, Rome, Italy., Vallese S; Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Ciolfi A; Molecular Genetics and Functional Genomics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Bisogno G; Pediatric Hematology-Oncology Division, University Hospital, Padova, Italy., Alaggio R; Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy., Tartaglia M; Molecular Genetics and Functional Genomics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
المصدر: The Journal of pathology [J Pathol] 2024 Jun; Vol. 263 (2), pp. 166-177. Date of Electronic Publication: 2024 Apr 17.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: John Wiley And Sons Country of Publication: England NLM ID: 0204634 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-9896 (Electronic) Linking ISSN: 00223417 NLM ISO Abbreviation: J Pathol Subsets: MEDLINE
أسماء مطبوعة: Publication: Chichester : John Wiley And Sons
Original Publication: London, Oliver & Boyd.
مواضيع طبية MeSH: Fibrosarcoma*/genetics , Fibrosarcoma*/pathology , Proto-Oncogene Proteins c-raf*/genetics , Oncogene Proteins, Fusion*/genetics , Nephroma, Mesoblastic*/genetics , Nephroma, Mesoblastic*/pathology, Humans ; Infant ; Female ; Male ; Kidney Neoplasms/genetics ; Kidney Neoplasms/pathology ; Gene Fusion ; Signal Transduction/genetics ; Proto-Oncogene Proteins c-ets/genetics ; Cell Proliferation ; Gene Rearrangement ; ETS Translocation Variant 6 Protein ; Receptor, trkC
مستخلص: 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.
(© 2024 The Pathological Society of Great Britain and Ireland.)
References: Coffin CM, Alaggio R. Fibroblastic and myofibroblastic tumors in children and adolescents. Pediatr Dev Pathol 2012; 15: 127–180.
Sultan I, Casanova M, Al‐Jumaily U, et al. Soft tissue sarcomas in the first year of life. Eur J Cancer 2010; 46: 2449–2456.
Knezevich SR, McFadden DE, Tao W, et al. A novel ETV6‐NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 1998; 18: 184–187.
Pavlick D, Schrock AB, Malicki D, et al. Identification of NTRK fusions in pediatric mesenchymal tumors. Pediatr Blood Cancer 2017; 64: e26433.
Tognon C, Garnett M, Kenward E, et al. The chimeric protein tyrosine kinase ETV6‐NTRK3 requires both Ras‐Erk1/2 and PI3‐kinase‐Akt signaling for fibroblast transformation. Cancer Res 2001; 61: 8909–8916.
Davis JL, Al‐Ibraheemi A, Rudzinski ER, et al. Mesenchymal neoplasms with NTRK and other kinase gene alterations. Histopathology 2022; 80: 4–18.
Kojima N, Mori T, Motoi T, et al. Frequent CD30 expression in an emerging group of mesenchymal tumors with NTRK, BRAF, RAF1, or RET fusions. Mod Pathol 2023; 36: 100083.
Warmke LM, Al‐Ibraheemi A, Wang L, et al. FGFR1 gene fusions in a subset of pediatric mesenchymal tumors: expanding the genetic spectrum of tumors sharing histologic overlap with infantile fibrosarcoma and ‘NTRK‐rearranged’ spindle cell neoplasms. Genes Chromosomes Cancer 2023; 62: 641–647.
Pfister SM, Reyes‐Múgica M, Chan JKC, et al. A summary of the inaugural WHO classification of pediatric tumors: transitioning from the optical into the molecular era. Cancer Discov 2022; 12: 331–355.
Penning AJ, Al‐Ibraheemi A, Michal M, et al. Novel BRAF gene fusions and activating point mutations in spindle cell sarcomas with histologic overlap with infantile fibrosarcoma. Mod Pathol 2021; 34: 1530–1540.
Suurmeijer AJH, Dickson BC, Swanson D, et al. A novel group of spindle cell tumors defined by S100 and CD34 co‐expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Genes Chromosomes Cancer 2018; 57: 611–621.
Coffin CM, Beadling C, Neff T, et al. Infantile fibrosarcoma with a novel RAF1 rearrangement: the contemporary challenge of reconciling classic morphology with novel molecular genetics. Hum Pathol: Case Rep 2020; 22: 200434.
Hicks JK, Henderson‐Jackson E, Duggan J, et al. Identification of a novel MTAP‐RAF1 fusion in a soft tissue sarcoma. Diagn Pathol 2018; 13: 77.
Mok Y, Kimpo MS, Chen H, et al. Spindle cell tumour with S100 and CD34 co‐expression showing PDZRN3‐RAF1 rearrangement – a recently described entity. Histopathology 2019; 74: 1109–1111.
Zhang T, Wang Q, Yi X, et al. RAF1‐rearranged spindle cell tumour: report of two additional cases with identification of a novel FMR1‐RAF1 fusion. Virchows Arch 2021; 479: 1245–1253.
Gong LH, Liu WF, Niu XH, et al. Two cases of spindle cell tumors with S100 and CD34 co‐expression showing novel RAF1 fusions. Diagn Pathol 2022; 17: 80.
Yeung MCF, Lam AYL, Shek TWH. Novel MAP4::RAF1 fusion in a primary bone sarcoma: expanding the spectrum of RAF1 fusion sarcoma. Int J Surg Pathol 2022; 30: 682–688.
Dermawan JK, DiNapoli SE, Sukhadia P, et al. Malignant undifferentiated epithelioid neoplasms with MAML2 rearrangements: a clinicopathologic study of seven cases demonstrating a heterogenous entity. Genes Chromosomes Cancer 2023; 62: 191–201.
Park E, Rawson S, Li K, et al. Architecture of autoinhibited and active BRAF‐MEK1‐14‐3‐3 complexes. Nature 2019; 575: 545–550.
Tran TH, Chan AH, Young LC, et al. KRAS interaction with RAF1 RAS‐binding domain and cysteine‐rich domain provides insights into RAS‐mediated RAF activation. Nat Commun 2021; 12: 1176.
Gibney GT, Messina JL, Fedorenko IV, et al. Paradoxical oncogenesis‐the long‐term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol 2013; 10: 390–399.
Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA‐seq aligner. Bioinformatics 2013; 29: 15–21.
Sahraeian SME, Mohiyuddin M, Sebra R, et al. Gaining comprehensive biological insight into the transcriptome by performing a broad‐spectrum RNA‐seq analysis. Nat Commun 2017; 8: 59.
Vu TN, Deng W, Trac QT, et al. A fast detection of fusion genes from paired‐end RNA‐seq data. BMC Genomics 2018; 19: 786.
Nicorici D, Satalan M, Edgren H, et al. FusionCatcher – a tool for finding somatic fusion genes in paired‐end RNA‐sequencing data. bioRxiv 2014; https://doi.org/10.1101/011650. [Not peer reviewed].
Rossi S, Barresi S, Colafati GS, et al. PATZ1‐rearranged tumors of the central nervous system: characterization of a pediatric series of seven cases. Mod Pathol 2023; 37: 100387.
Cordeddu V, Di Schiavi E, Pennacchio LA, et al. Mutation of SHOC2 promotes aberrant protein N‐myristoylation and causes Noonan‐like syndrome with loose anagen hair. Nat Genet 2009; 41: 1022–1026.
Motta M, Fasano G, Gredy S, et al. SPRED2 loss‐of‐function causes a recessive Noonan syndrome‐like phenotype. Am J Hum Genet 2021; 108: 2112–2129.
Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161: 1215–1228.
Hayward NK, Wilmott JS, Waddell N, et al. Whole‐genome landscapes of major melanoma subtypes. Nature 2017; 545: 175–180.
Hartmaier RJ, Albacker LA, Chmielecki J, et al. High‐throughput genomic profiling of adult solid tumors reveals novel insights into cancer pathogenesis. Cancer Res 2017; 77: 2464–2475.
McEvoy CR, Xu H, Smith K, et al. Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4‐RAF1 fusion. J Clin Invest 2019; 129: 1940–1945.
LeBlanc RE, Lefferts JA, Baker ML, et al. Novel LRRFIP2‐RAF1 fusion identified in an acral melanoma: a review of the literature on melanocytic proliferations with RAF1 fusions and the potential therapeutic implications. J Cutan Pathol 2020; 47: 1181–1186.
Jones DTW, Kocialkowski S, Liu L, et al. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 2009; 28: 2119–2123.
Palanisamy N, Ateeq B, Kalyana‐Sundaram S, et al. Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 2010; 16: 793–798.
Chmielecki J, Hutchinson KE, Frampton GM, et al. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov 2014; 4: 1398–1405.
Punekar SR, Velcheti V, Neel BG, et al. The current state of the art and future trends in RAS‐targeted cancer therapies. Nat Rev Clin Oncol 2022; 19: 637–655.
Ehrenreiter K, Piazzolla D, Velamoor V, et al. Raf‐1 regulates rho signaling and cell migration. J Biol Chem 2005; 168: 955–964.
Tian H, Yin L, Ding K, et al. Raf1 is a prognostic factor for progression in patients with non‐small cell lung cancer after radiotherapy. Oncol Rep 2018; 39: 1966–1974.
WHO classification of Tumors. Soft Tissue and Bone Tumours. IARC: Lyon, 2020.
Ross JS, Wang K, Chmielecki J, et al. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy. Int J Cancer 2016; 138: 881–890.
Panet F, Jung S, Alcindor T. Sustained response to the mitogen‐activated extracellular kinase inhibitor trametinib in a spindle cell sarcoma harboring a QKI‐RAF1 gene fusion. JCO Precis Oncol 2022; 6: e2100303.
Izumi H, Matsumoto S, Liu J, et al. The CLIP1‐LTK fusion is an oncogenic driver in non‐small‐cell lung cancer. Nature 2021; 600: 319–323.
Vujanić GM, Gessler M, Ooms AHAG, et al. The UMBRELLA SIOP‐RTSG 2016 Wilms tumour pathology and molecular biology protocol. Nat Rev Urol 2018; 15: 693–701.
Terwisscha van Scheltinga CEJ, Wijnen MHWA, Martelli H, et al. In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: analysis of the EpSSG RMS 2005 study. Eur J Surg Oncol 2022; 48: 1536–1542.
معلومات مُعتمدة: 28768 Associazione Italiana per la Ricerca sul Cancro; Ministero della Salute
فهرسة مساهمة: Keywords: MAPK signaling; PI3K‐AKT signaling; RAF kinase; fusion proteins; infantile fibrosarcoma
المشرفين على المادة: EC 2.7.11.1 (Raf1 protein, human)
EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
0 (Oncogene Proteins, Fusion)
0 (Proto-Oncogene Proteins c-ets)
0 (ETV6-NTRK3 fusion protein, human)
0 (ETS Translocation Variant 6 Protein)
EC 2.7.10.1 (Receptor, trkC)
تواريخ الأحداث: Date Created: 20240417 Date Completed: 20240509 Latest Revision: 20240605
رمز التحديث: 20240605
DOI: 10.1002/path.6272
PMID: 38629245
قاعدة البيانات: MEDLINE
الوصف
تدمد:1096-9896
DOI:10.1002/path.6272