TY - JOUR
T1 - Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma
AU - Tanas, Munir R.
AU - Sboner, Andrea
AU - Oliveira, Andre M.
AU - Erickson-Johnson, Michele R.
AU - Hespelt, Jessica
AU - Hanwright, Philip J.
AU - Flanagan, John
AU - Luo, Yuling
AU - Fenwick, Kerry
AU - Natrajan, Rachael
AU - Mitsopoulos, Costas
AU - Zvelebil, Marketa
AU - Hoch, Benjamin L.
AU - Weiss, Sharon W.
AU - Debiec-Rychter, Maria
AU - Sciot, Raf
AU - West, Rob B.
AU - Lazar, Alexander J.
AU - Ashworth, Alan
AU - Reis-Filho, Jorge S.
AU - Lord, Christopher J.
AU - Gerstein, Mark B.
AU - Rubin, Mark A.
AU - Rubin, Brian P.
PY - 2011/8/31
Y1 - 2011/8/31
N2 - 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 breakapart 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.
AB - 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 breakapart 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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U2 - 10.1126/scitranslmed.3002409
DO - 10.1126/scitranslmed.3002409
M3 - Article
C2 - 21885404
AN - SCOPUS:80052349902
SN - 1946-6234
VL - 3
JO - Science translational medicine
JF - Science translational medicine
IS - 98
M1 - 98ra82
ER -