title: RET fusion as a novel driver of medullary thyroid carcinoma.
abstract: BACKGROUND
  Oncogenic RET tyrosine kinase gene fusions and activating mutations have recently been identified in lung cancers, prompting initiation of targeted therapy trials in this disease. Although RET point mutation has been identified as a driver of tumorigenesis in medullary thyroid carcinoma (MTC), no fusions have been described to date.
  
  
  OBJECTIVE
  We evaluated the role of RET fusion as an oncogenic driver in MTC.
  
  
  METHODS
  We describe a patient who died from aggressive sporadic MTC < 10 months after diagnosis. Her tumor was evaluated by means of next-generation sequencing, including an intronic capture strategy.
  
  
  RESULTS
  A reciprocal translocation involving RET intron 12 was identified. The fusion was validated using a targeted break apart fluorescence in situ hybridization probe, and RNA sequencing confirmed the existence of an in-frame fusion transcript joining MYH13 exon 35 with RET exon 12. Ectopic expression of fusion product in a murine Ba/F3 cell reporter model established strong oncogenicity. Three tyrosine kinase inhibitors currently used to treat MTC in clinical practice blocked tumorigenic cell growth.
  
  
  CONCLUSIONS
  This finding represents the report of a novel RET fusion, the first of its kind described in MTC. The finding of this potential novel oncogenic mechanism has clear implications for sporadic MTC, which in the majority of cases has no driver mutation identified. The presence of a RET fusion also provides a plausible target for RET tyrosine kinase inhibitor therapies.
authors.affiliation: Departments of Surgical Oncology (E.G.G., J.B., J.E.L., F.M.-B., N.D.P.), Institute of Personalized Cancer Therapy (P.K.-S.N., K.R.S.), Endocrine Neoplasia and Hormonal Disorders (N.L.B., S.G.W., G.J.C.), Bioinformatics and Computational Biology (K.C.), Hematopathology (X.L.), Investigational Cancer Therapeutics (F.M.-B.), Systems Biology (G.B.M.), and Pathology (M.D.W.), University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Foundation Medicine (G.P., R.Y.), Cambridge, Massachusetts 02141; and Integrative Molecular and Biomedical Sciences Graduate Program (H.L., K.L.S.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Grubbs
authors.forename: Patrick Kwok-Shing
authors.initials: PK
authors.lastname: Ng
authors.forename: Jacquelin
authors.initials: J
authors.lastname: Bui
authors.forename: Naifa L
authors.initials: NL
authors.lastname: Busaidy
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
authors.forename: Xinyan
authors.initials: X
authors.lastname: Lu
authors.forename: Hengyu
authors.initials: H
authors.lastname: Lu
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Gary
authors.initials: G
authors.lastname: Palmer
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Perrier
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Scott
authors.forename: Kenna R
authors.initials: KR
authors.lastname: Shaw
authors.forename: Steven G
authors.initials: SG
authors.lastname: Waguespack
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Williams
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Cote
mesh_terms: D018278:Carcinoma, Neuroendocrine; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C510866:MYH13 protein, human; D015514:Oncogene Proteins, Fusion; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D018995:Myosin Heavy Chains