Article

Identification of disease-defining gene fusion in epithelioid hemangioendothelioma

Department of Molecular Genetics and Anatomic Pathology, Lerner Research Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Science translational medicine (Impact Factor: 14.41). 08/2011; 3(98):98ra82. DOI: 10.1126/scitranslmed.3002409
Source: PubMed

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.

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    • "RNA-seq experiments for the identification of chimeric transcripts (Tanas et al., 2011; Pierron et al., 2012; Mosquera et al., 2013). Briefly, paired-end reads mapped to different genes are first used to identify potential chimeric candidates. "
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