The FET protein family (also known as the TET protein family)[1] consists of three similarly structured and functioning proteins.[2] They and the genes in the FET gene family which encode them (i.e. form the pre-messenger RNAs that are converted to the messenger RNAs responsible for their production) are:[2][3] 1) the EWSR1 protein encoded by the EWSR1 gene (also termed the Ewing sarcoma RNA binding protein, EWS RNA binding protein 1, or bK984G1.4 gene) located at band 12.2 of the long (i.e. "q") arm of chromosome 22;[4] 2) the FUS (i.e. fused in sarcoma) protein encoded by the FUS gene (also termed the FUS RNA binding protein, TLS, asTLS, ALS6, ETM4, FUS1, POMP75, altFUS, or HNRNPP2 gene) located at band 16 on the short arm of chromosome 16;[5] and 3) the TAF15 protein encoded by the TAF15 gene (also termed the TATA-box binding protein associated factor 15, Npl3, RBP56, TAF2N, or TAFII68 gene) located at band 12 on the long arm of chromosome 7[6] The FET in this protein family's name derives from the first letters of FUS, EWSR1, and TAF15.[7]

FET proteins are abundantly expressed in virtually all tissues examined. They are RNA-binding proteins.[7] By binding to their RNA targets, they contribute to the regulation of: a) the transcription of genes into pre-messenger RNA, the splicing of pre-messenger RNA into mature messenger RNA, and the transport of these RNAs between different areas of their parent cells; b) the processing of micro-RNAs that are involved in RNA silencing and post-transcriptional regulation of gene expression; and 3) the detection and repair of damaged DNA. Through these multiple, complex, and often incompletely understood actions, the FET family proteins regulate the cellular expression of diverse genes.[2] However, the genes for FET proteins often undergo various types of mutation. While these mutations and the diseases with which they are associated can be found in the Wikipedia pages on these diseases, this article focuses on one type of mutation, the fusion gene mutation. Fusion genes are formed from two previously independent genes that become united due to a chromosome translocation, deletion of some genetic material in a chromosome, or chromosomal inversion.[1][8] For example, the EWSR1-FL1[9] fusion gene is made by a chromosomal translocation which merges part of the EWSR1 gene normally located on band 12 of the long (or "q") arm of chromosome 22 with part of the FLI1 ETS transcription factor family gene normally located on band 24 of the long arm of chromosome 11. The EWSR1-FLI1 fusion gene encodes an EWS-FLI1 chimeric protein which possesses unregulated and excessive FLI1 transcription factor activity which it appears to contribute to the development of Ewing sarcomas.[10] FET fusion genes have attracted recent interest because they have been found to be associated with, and may act to promote the development of, a wide range of soft tissue neoplasms derived from mesencyhmal tissue cells.[3][7][11] Detection of a FET gene–containing fusion gene is extremely helpful in diagnosing tumor types,[1][11] defining the pathogenic mechanisms by which these fusion proteins promote disorders,[3][12] and thereby identifying potential targets for treating these disorders.[2][13] The following are examples of these fusion genes' associations with malignant and benign neoplastic tumors.[1][7]

Malignant neoplasms

  • Ewing sarcoma: Almost all cases of the classical form of the Ewing sarcomas have tumor cells that express a fusion gene that merges part of a FET family gene with part of an ETS transcription factor family gene (i.e. a FLI1, ERG, ETV1, ETV4, or FEV[14] gene).[15] These fusion genes are the EWSR1–FLI1 fusion gene in 80-85% of cases or EWSR1-ERG fusion gene in 5 to 10% of cases. Rare cases of classical Ewing sarcoma tumor cells express an EWSR1 or FUS gene fused to an ETV1, ETV4, or FEV gene.[1] The neoplastic cells in the round cell sarcoma variant of the Ewing sarcomas (sometimes termed NFATC2-rearranged sarcomas) express fusion genes composed of an FET family gene fused to a gene that is not a ETS transcription family gene. These fusion genes are EWSR1-NFATC2, FUS-NFATC2, and EWSR1-PATZ1.[16]
  • Desmoplastic small-round-cell tumors: These tumors' neoplastic cells consistently express the EWSR1-WT1 fusion gene.[1][17]
  • Myxoid liposarcoma: these tumors' neoplastic cells express the FUS-DDIT3 fusion gene in 90% or the EWSR1-DDIT3 fusion gene in rare cases of the disease.[1][18]
  • Angiomatoid fibrous histiocytoma: The neoplastic cells in these tumors express a EWSR1-CREB1 fusion gene in most cases or a EWSR1-CREB, FUS-CREB, EWSR1-ATF1, FUS-ATF1, WSR1-CREM, or FUS-CREM fusion gene in uncommon cases of the disease.[1][19]
  • Intracranial mesenchymal tumors with FET‐CREB fusions: These tumors are suggested to be a variant of the angiomatoid fibrous histiocytoma tumors. By definition, the neoplastic cells in all of these tumors express FET-CREB fusion genes. Of 20 reported cases, the fusion genes in these tumors' neoplastic cells were the EWSR1‐ATF1 (8 cases), EWSR1‐CREB1 (7 cases), EWSR1‐CREM (4 cases), and FUS‐CREM (1 case).[20]
  • Primary pulmonary myxoid sarcoma: Among 27 reported cases of these extremely rare tumors, 17 expressed the EWSR1-CREB1 and 1 expressed a not further defined EWSR1 gene rearrangement in their neoplastic cells.[21]
  • Clear cell sarcomas: This tumors' neoplastic cells expressed the EWSR1-ATF1 fusion gene in a majority of cases or a EWSR1-CREB1, EWSR1-CREM,[22] or EWSR1-DDIT3[1] fusion gene in a small subset of cases.
  • Clear cell sarcoma-like gastrointestinal tumor (also termed gastrointestinal neuroectodermal tumor): The neoplastic cells in these tumors express an EWSR1:ATF1 or EWSR1:CREB1 fusion genes in >50% or ~25% of cases, respectively.[1][23]
  • Mesothelioma: A small subset of these tumors have neoplastic cells that express a EWSR1-CREB fusion gene or, in fewer cases, a FUS-CREB fusion gene.[1][22]
  • Myoepithelioma: About 50% of these tumors have neoplastic cells which express a fusion gene consisting of a EWSR1 gene fused to a PBX1, PBX3, ZNF444,[24] POU5F1, ATF1, or KLF17 gene or in less common cases a FUS gene fused to one of the latter genes.[1]
  • Sclerosing epithelioid fibrosarcoma: The neoplastic cells in these tumors express the EWSR1-CREB3L1 fusion gene in ~30%, the FUS-CREB3L2 fusion gene in 12%, and the EWSR1-CREB3L2,[25] EWSR1-CREB3L3,[26] or EWSR1-CREM fusion gene in rare cases of the disease,[27] and other as yet not fully defined rearrangements in the EWSR1 gene.[25]
  • Low-grade fibromyxoid sarcoma: The neoplastic cells in these tumors express the FUS-CREB3L2 fusion gene in the majority or the FUS-CREB3L1,[28] EWSR1-CREB3L2, or EWSR2-CREBL1[1] fusion gene in a minority of cases.
  • Extraskeletal myxoid chondrosarcoma: These tumors' neoplastic cells express the EWSR1-NR4A3 fusion gene in most cases or the TAF15-NR4A3 in occasional cases of the disease.[1]
  • EWSR1-SMAD3-positive fibroblastic tumor: These tumors, which are a recently characterized neoplasm with distinct clinicopathologic features,[29] are currently defined by the expression of the EWSR1-SMAD3 fusion gene in their neoplastic cells.[1]
  • Epithelioid and spindle cell rhabdomyosarcoma with EWSR1/FUS-TFCP2 Fusion: These newly described tumors[30] are regarded as a small subset of the rhabdomyosarcomas that by definition contain neoplastic cells that express the EWSR1-TFCP2 or FUS-TFCP2 fusion gene.[1]

Benign neoplasms

  • Simple bone cyst (also termed unicameral bone cysts): A subset of these tumors contain neoplastic cells that express the FUS-NFATC2 or EWSR1-NFATC2 fusion gene.[1] A recent study reported that the neoplastic cells in these cysts expressed a FUS-NFATC2 fusion gene in four and the EWSR1-NFATC2 fusion gene in two of nine test cases.[31]
  • Hemangioma of bone with an EWSR1-NFATC1 Fusion: These rare tumors[32] are a subset of hemangiomas that by definition are in bone tissues and consist of neoplastic cells that express the EWSR1-NFATC1 fusion gene.[1]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Flucke U, van Noesel MM, Siozopoulou V, Creytens D, Tops BB, van Gorp JM, Hiemcke-Jiwa LS (June 2021). "EWSR1-The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review". Diagnostics (Basel, Switzerland). 11 (6): 1093. doi:10.3390/diagnostics11061093. PMC 8232650. PMID 34203801.
  2. 1 2 3 4 Kovar H (2011). "Dr. Jekyll and Mr. Hyde: The Two Faces of the FUS/EWS/TAF15 Protein Family". Sarcoma. 2011: 837474. doi:10.1155/2011/837474. PMC 3005952. PMID 21197473.
  3. 1 2 3 Lindén M, Thomsen C, Grundevik P, Jonasson E, Andersson D, Runnberg R, Dolatabadi S, Vannas C, Luna Santamaria M, Fagman H, Ståhlberg A, Åman P (May 2019). "FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex". EMBO Reports. 20 (5). doi:10.15252/embr.201845766. PMC 6500973. PMID 30962207.
  4. ↑ "EWSR1 EWS RNA binding protein 1 [Homo sapiens (Human)] - Gene - NCBI".
  5. ↑ "FUS FUS RNA binding protein [Homo sapiens (Human)] - Gene - NCBI".
  6. ↑ "TAF15 TATA-box binding protein associated factor 15 [Homo sapiens (Human)] - Gene - NCBI".
  7. 1 2 3 4 Hoell JI, Larsson E, Runge S, Nusbaum JD, Duggimpudi S, Farazi TA, Hafner M, Borkhardt A, Sander C, Tuschl T (November 2011). "RNA targets of wild-type and mutant FET family proteins". Nature Structural & Molecular Biology. 18 (12): 1428–31. doi:10.1038/nsmb.2163. PMC 3230689. PMID 22081015.
  8. ↑ Boone MA, Taslim C, Crow JC, Selich-Anderson J, Watson M, Heppner P, Hamill J, Wood AC, Lessnick SL, Winstanley M (August 2021). "Identification of a novel FUS/ETV4 fusion and comparative analysis with other Ewing sarcoma fusion proteins". Molecular Cancer Research. 19 (11): 1795–1801. doi:10.1158/1541-7786.MCR-21-0354. PMC 8568690. PMID 34465585. S2CID 237373339.
  9. ↑ "FL1 Follicular lymphoma, susceptibility to, 1 [Homo sapiens (Human)] - Gene - NCBI".
  10. ↑ Sbaraglia M, Righi A, Gambarotti M, Dei Tos AP (January 2020). "Ewing sarcoma and Ewing-like tumors". Virchows Archiv. 476 (1): 109–119. doi:10.1007/s00428-019-02720-8. PMID 31802230. S2CID 208613433.
  11. 1 2 Krystel-Whittemore M, Taylor MS, Rivera M, Lennerz JK, Le LP, Dias-Santagata D, Iafrate AJ, Deshpande V, Chebib I, Nielsen GP, Wu CL, Nardi V (November 2019). "Novel and established EWSR1 gene fusions and associations identified by next-generation sequencing and fluorescence in-situ hybridization". Human Pathology. 93: 65–73. doi:10.1016/j.humpath.2019.08.006. PMID 31430493. S2CID 201117873.
  12. ↑ Agaimy A (January 2020). "What is new in epithelioid soft tissue tumors?". Virchows Archiv. 476 (1): 81–96. doi:10.1007/s00428-019-02677-8. PMID 31686193. S2CID 207893952.
  13. ↑ Tanaka M, Nakamura T (July 2021). "Modeling fusion gene-associated sarcoma: Advantages for understanding sarcoma biology and pathology". Pathology International. 71 (10): 643–654. doi:10.1111/pin.13142. PMID 34265156. S2CID 235962562.
  14. ↑ "FEV FEV transcription factor, ETS family member [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  15. ↑ Durer, S.; Shaikh, H. (2021). "Ewing Sarcoma". StatPearls. StatPearls. PMID 32644609.
  16. ↑ Perret R, Escuriol J, Velasco V, Mayeur L, Soubeyran I, Delfour C, Aubert S, Polivka M, Karanian M, Meurgey A, Le Guellec S, Weingertner N, Hoeller S, Coindre JM, Larousserie F, Pierron G, Tirode F, Le Loarer F (October 2020). "NFATc2-rearranged sarcomas: clinicopathologic, molecular, and cytogenetic study of 7 cases with evidence of AGGRECAN as a novel diagnostic marker". Modern Pathology. 33 (10): 1930–1944. doi:10.1038/s41379-020-0542-z. PMID 32327700. S2CID 216085279.
  17. ↑ Baisakh MR, Tiwari A, Gandhi JS, Naik S, Sharma SK, Balzer BL, Sharma S, Peddinti K, Jha S, Sahu PK, Pradhan D, Geller M, Amin MB, Dhillon J, Mohanty SK (October 2020). "Primary round cell sarcomas of the urinary bladder with EWSR1 rearrangement: a multi-institutional study of thirteen cases with a review of the literature". Human Pathology. 104: 84–95. doi:10.1016/j.humpath.2020.08.001. PMID 32798549. S2CID 221143155.
  18. ↑ Owen I, Yee D, Wyne H, Perdikari TM, Johnson V, Smyth J, Kortum R, Fawzi NL, Shewmaker F (September 2021). "The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid-liquid phase separation". Journal of Cell Science. 134 (17). doi:10.1242/jcs.258578. PMC 8445604. PMID 34357401.
  19. ↑ Wang Z, Zhang L, Ren L, Liu D, Du J, Zhang M, Lou G, Song Y, Wang Y, Wu C, Han G (February 2021). "Distinct clinicopathological features of pulmonary primary angiomatoid fibrous histiocytoma: A report of four new cases and review of the literature". Thoracic Cancer. 12 (3): 314–323. doi:10.1111/1759-7714.13727. PMC 7862796. PMID 33314685.
  20. ↑ Sloan EA, Chiang J, Villanueva-Meyer JE, Alexandrescu S, Eschbacher JM, Wang W, Mafra M, Ud Din N, Carr-Boyd E, Watson M, Punsoni M, Oviedo A, Gilani A, Kleinschmidt-DeMasters BK, Coss DJ, Lopes MB, Raffel C, Berger MS, Chang SM, Reddy A, Ramani B, Ferris SP, Lee JC, Hofmann JW, Cho SJ, Horvai AE, Pekmezci M, Tihan T, Bollen AW, Rodriguez FJ, Ellison DW, Perry A, Solomon DA (July 2021). "Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms". Brain Pathology (Zurich, Switzerland). 31 (4): e12918. doi:10.1111/bpa.12918. PMC 8089120. PMID 33141488.
  21. ↑ Chen Z, Yang Y, Chen R, Ng CS, Shi H (February 2020). "Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion: a case report and review of the literature". Diagnostic Pathology. 15 (1): 15. doi:10.1186/s13000-020-00930-2. PMC 7008573. PMID 32039736.
  22. 1 2 Argani P, Harvey I, Nielsen GP, Takano A, Suurmeijer AJ, Voltaggio L, Zhang L, Sung YS, Stenzinger A, Mechtersheimer G, Dickson BC, Antonescu CR (November 2020). "EWSR1/FUS-CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities". Modern Pathology. 33 (11): 2233–2243. doi:10.1038/s41379-020-0646-5. PMC 7584759. PMID 32770123.
  23. ↑ Sivasubramaniam P, Tiegs-Heiden CA, Sturgis CD, Hagen CE, Hartley CP, Thangaiah JJ (September 2021). "Malignant gastrointestinal neuroectodermal tumor: Cytologic, histologic, immunohistochemical, and molecular pitfalls". Annals of Diagnostic Pathology. 55: 151813. doi:10.1016/j.anndiagpath.2021.151813. PMID 34509898. S2CID 237493040.
  24. ↑ "ZNF444 zinc finger protein 444 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  25. 1 2 Porteus C, Gan Q, Gong Y, Pantanowitz L, Henderson-Jackson E, Saeed-Vafa D, Mela N, Peterson D, Ahmad N, Ahmed A, Bui M (2020). "Sclerosing epithelioid fibrosarcoma: cytologic characterization with histologic, immunohistologic, molecular, and clinical correlation of 8 cases". Journal of the American Society of Cytopathology. 9 (6): 513–519. doi:10.1016/j.jasc.2020.05.005. PMID 32624384. S2CID 220369922.
  26. ↑ "CREB3L2 cAMP responsive element binding protein 3 like 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
  27. ↑ Martínez-Trufero J, Cruz Jurado J, Gómez-Mateo MC, Bernabeu D, Floría LJ, Lavernia J, Sebio A, García Del Muro X, Álvarez R, Correa R, Hernández-León CN, Marquina G, Hindi N, Redondo A, Martínez V, Asencio JM, Mata C, Valverde Morales CM, Martin-Broto J (September 2021). "Uncommon and peculiar soft tissue sarcomas: Multidisciplinary review and practical recommendations for diagnosis and treatment. Spanish group for Sarcoma research (GEIS - GROUP). Part I". Cancer Treatment Reviews. 99: 102259. doi:10.1016/j.ctrv.2021.102259. PMID 34311246.
  28. ↑ Sambri A, Righi A, Tuzzato G, Donati D, Bianchi G (2018). "Low-grade fibromyxoid sarcoma of the extremities: a clinicopathologic study of 24 cases and review of the literature". Polish Journal of Pathology. 69 (3): 219–225. doi:10.5114/pjp.2018.79541. hdl:11585/667908. PMID 30509048.
  29. ↑ Foot O, Hallin M, Jones RL, Sumathi VP, Thway K (April 2021). "EWSR1-SMAD3-Positive Fibroblastic Tumor". International Journal of Surgical Pathology. 29 (2): 179–181. doi:10.1177/1066896920938124. PMID 32615834. S2CID 220326585.
  30. ↑ Chrisinger JS, Wehrli B, Dickson BC, Fasih S, Hirbe AC, Shultz DB, Zadeh G, Gupta AA, Demicco EG (November 2020). "Epithelioid and spindle cell rhabdomyosarcoma with FUS-TFCP2 or EWSR1-TFCP2 fusion: report of two cases". Virchows Archiv. 477 (5): 725–732. doi:10.1007/s00428-020-02870-0. PMID 32556562. S2CID 219872625.
  31. ↑ Pižem J, Šekoranja D, Zupan A, Boštjančič E, Matjašič A, Mavčič B, Contreras JA, Gazič B, Martinčič D, Snoj Ž, Limpel Novak KA, Salapura V (December 2020). "FUS-NFATC2 or EWSR1-NFATC2 Fusions Are Present in a Large Proportion of Simple Bone Cysts". The American Journal of Surgical Pathology. 44 (12): 1623–1634. doi:10.1097/PAS.0000000000001584. PMID 32991339. S2CID 222166961.
  32. ↑ Arbajian E, Magnusson L, Brosjö O, Wejde J, Folpe AL, Nord KH, Mertens F (April 2013). "A benign vascular tumor with a new fusion gene: EWSR1-NFATC1 in hemangioma of the bone". The American Journal of Surgical Pathology. 37 (4): 613–6. doi:10.1097/PAS.0b013e31827ae13b. PMID 23480895. S2CID 26564119.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.