title: Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma.
abstract: Integrating transcriptomic sequencing with conventional cytogenetics, we identified WWTR1 (WW domain-containing transcription regulator 1) (3q25) and CAMTA1 (calmodulin-binding transcription activator 1) (1p36) as the two genes involved in the t(1;3)(p36;q25) chromosomal translocation that is characteristic of epithelioid hemangioendothelioma (EHE), a vascular sarcoma. This WWTR1/CAMTA1 gene fusion is under the transcriptional control of the WWTR1 promoter and encodes a putative chimeric transcription factor that joins the amino terminus of WWTR1, a protein that is highly expressed in endothelial cells, in-frame to the carboxyl terminus of CAMTA1, a protein that is normally expressed only in brain. Thus, CAMTA1 expression is activated inappropriately through a promoter-switch mechanism. The gene fusion is present in virtually all EHEs tested but is absent from all other vascular neoplasms, demonstrating it to be a disease-defining genetic alteration. A sensitive and specific break-apart fluorescence in situ hybridization assay was also developed to detect the translocation and will assist in the evaluation of this diagnostically challenging neoplasm. The chimeric WWTR1/CAMTA1 transcription factor may represent a therapeutic target for EHE and offers the opportunity to shed light on the functions of two poorly characterized proteins.
authors: Department of Molecular Genetics and Anatomic Pathology, Lerner Research Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Munir R
authors: MR
authors: Tanas
authors: Andrea
authors: A
authors: Sboner
authors: Andre M
authors: AM
authors: Oliveira
authors: Michele R
authors: MR
authors: Erickson-Johnson
authors: Jessica
authors: J
authors: Hespelt
authors: Philip J
authors: PJ
authors: Hanwright
authors: John
authors: J
authors: Flanagan
authors: Yuling
authors: Y
authors: Luo
authors: Kerry
authors: K
authors: Fenwick
authors: Rachael
authors: R
authors: Natrajan
authors: Costas
authors: C
authors: Mitsopoulos
authors: Marketa
authors: M
authors: Zvelebil
authors: Benjamin L
authors: BL
authors: Hoch
authors: Sharon W
authors: SW
authors: Weiss
authors: Maria
authors: M
authors: Debiec-Rychter
authors: Raf
authors: R
authors: Sciot
authors: Rob B
authors: RB
authors: West
authors: Alexander J
authors: AJ
authors: Lazar
authors: Alan
authors: A
authors: Ashworth
authors: Jorge S
authors: JS
authors: Reis-Filho
authors: Christopher J
authors: CJ
authors: Lord
authors: Mark B
authors: MB
authors: Gerstein
authors: Mark A
authors: MA
authors: Rubin
authors: Brian P
authors: BP
authors: Rubin
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019457:Chromosome Breakage; D020732:Cytogenetic Analysis; D020869:Gene Expression Profiling; D050939:Gene Fusion / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D018323:Hemangioendothelioma, Epithelioid / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: C487554:CAMTA1 protein, human; D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human