ETV6-NTRK3 gene fusion

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ETV6-NTRK3 gene fusion is the translocation of genetic material between the ETV6 gene located on the short arm (designated p) of chromosome 12 at position p13.2 (i.e. 12p13.2) and the NTRK3 gene located on the long arm (designated q) of chromosome 15 at position q25.3 (i.e. 15q25.3) to create the (12;15)(p13;q25) fusion gene, ETV6-NTRK3. This new gene consists of the 5' end of ETV6 fused to the 3' end of NTRK3.[1] ETV6-NTRK3 therefore codes for an chimeric oncoprotein consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the tyrosine kinase (i.e. PTK) domain of the NTRK3 protein.[2] The ETV6 gene codes for the transcription factor protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal hematopoiesis as well as the development and maintenance of the vascular network.[3] NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells. The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phophorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous.[4][5] Indeed, the ETV6-NTRK3 fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital fibrosarcoma[1] and subsequently found in secretory breast cancer (also termed juvenile breast cancer), Mammary analogue secretory carcinoma of salivary glands (also termed MASC or MASCSG), congenital fibrosarcoma, congenital mesoblastic nephroma, rare cases of acute myelogenous leukemia, ALK-negative Inflammatory myofibroblastic tumour, and radiation-induced papillary thyroid carcinoma.[6][7][8][9][10]

NTRK3 inhibitors in clinical development[edit]

Because cancers associated with the expression of the ETV6-NTRK3 fusion protein are known or suspected of being a direct consequence of overly active ETV6-NTRK6's tyrosine kinase, it has been proposed that tyrosine kinase inhibitors with specificity for NTRK3 may be of therapeutic usefulness in these cancers. Entrectinib is a pan-NTRK as well as an ALK and ROS1 tyrosine kinase inhibitor has been found useful in treating a single patient with ETV6-NRTK3 fusion gene-associated mammary analogue secretory carcinoma and has lend support to the clinical development of NTRK3-directed tyrosine kinase inhibitors to treat ETV6-NTRK3 fusion protein associated malignancies.[9] Three clinical trials are in the recruitment phase for determining the efficacy of treating a wide range of solid tumors associated with mutated overactive tyrosine kinase proteins, including the ETV6-TRK3 protein, with larotrectinib, a non-selective inhibitor of NTRK1, NTRK2, and NTRK3 tyrosine kinases.[11]

References[edit]

  1. ^ a b Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH (18 Feb 1998). "A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma". Nat Genet. 18 (2): 184–7. PMID 9462753. doi:10.1038/ng0298-184. 
  2. ^ Wai DH, Knezevich SR, Lucas T, Jansen B, Kay RJ, Sorensen PH (Feb 17, 2000). "The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells". Oncogene. 19 (19(7)): 906–15. PMID 10702799. doi:10.1038/sj.onc.1203396. 
  3. ^ De Braekeleer E, Douet-Guilbert N, Morel F, Le Bris MJ, Basinko A, De Braekeleer M (2012). "ETV6 fusion genes in hematological malignancies: a review". Leukemia Research. 36 (8): 945–61. PMID 22578774. doi:10.1016/j.leukres.2012.04.010. 
  4. ^ Stenman G (2013). "Fusion oncogenes in salivary gland tumors: molecular and clinical consequences". Head and Neck Pathology. 7 Suppl 1: S12–9. PMC 3712096Freely accessible. PMID 23821214. doi:10.1007/s12105-013-0462-z. 
  5. ^ Lu H, Villafane N, Dogruluk T, Grzeskowiak CL, Kong K, Tsang YH, Zagorodna O, Pantazi A, Yang L, Neill NJ, Kim YW, Creighton CJ, Verhaak RG, Mills GB, Park P, Kucherlapati RS, Scott KL (2017). "Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer". Cancer Research. PMID 28512244. doi:10.1158/0008-5472.CAN-16-2745. 
  6. ^ Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH (Nov 2002). "Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma". Cancer Cell. 2 (5): 367–76. PMID 12450792. doi:10.1016/S1535-6108(02)00180-0. 
  7. ^ Majewska H, Skálová A, Stodulski D, Klimková A, Steiner P, Stankiewicz C, Biernat W. "Mammary analogue secretory carcinoma of salivary glands: a new entity associated with ETV6 gene rearrangement." Virchows Arch. 2015 Mar;466(3):245-54. doi: 10.1007/s00428-014-1701-8. Epub 2014 Dec 12.
  8. ^ Argani, P.; Fritsch, M.; Kadkol, S. S.; Schuster, A.; Beckwith, J. B.; Perlman, E. J. (2000-01-01). "Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular congenital mesoblastic nephroma in paraffin-embedded tissue: application to challenging pediatric renal stromal tumors". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 13 (1): 29–36. ISSN 0893-3952. PMID 10658907. doi:10.1038/modpathol.3880006. 
  9. ^ a b Khotskaya YB, Holla VR, Farago AF, Mills Shaw KR, Meric-Bernstam F, Hong DS (2017). "Targeting TRK family proteins in cancer". Pharmacology & Therapeutics. 173: 58–66. PMID 28174090. doi:10.1016/j.pharmthera.2017.02.006. 
  10. ^ Skalova A, Michal M, Simpson RH (2017). "Newly described salivary gland tumors". Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. 30 (s1): S27–S43. PMID 28060365. doi:10.1038/modpathol.2016.167. 
  11. ^ https://clinicaltrials.gov/ct2/results?term=ETV6-NTRK3&Search=Search