Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma - PubMed (original) (raw)

. 2011 Aug 31;3(98):98ra82.

doi: 10.1126/scitranslmed.3002409.

Andrea Sboner, Andre M Oliveira, Michele R Erickson-Johnson, Jessica Hespelt, Philip J Hanwright, John Flanagan, Yuling Luo, Kerry Fenwick, Rachael Natrajan, Costas Mitsopoulos, Marketa Zvelebil, Benjamin L Hoch, Sharon W Weiss, Maria Debiec-Rychter, Raf Sciot, Rob B West, Alexander J Lazar, Alan Ashworth, Jorge S Reis-Filho, Christopher J Lord, Mark B Gerstein, Mark A Rubin, Brian P Rubin

Affiliations

Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma

Munir R Tanas et al. Sci Transl Med. 2011.

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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