Identification of a Disease-Defining Gene Fusion in Epithelioid Hemangioendothelioma SCIENCE TRANSLATIONAL MEDICINE Tanas, M. R., Sboner, A., Oliveira, A. M., Erickson-Johnson, M. R., Hespelt, J., Hanwright, P. J., Flanagan, J., Luo, Y., Fenwick, K., Natrajan, R., Mitsopoulos, C., Zvelebil, M., Hoch, B. L., Weiss, S. W., Debiec-Rychter, M., Sciot, R., West, R. B., Lazar, A. J., Ashworth, A., Reis-Filho, J. S., Lord, C. J., Gerstein, M. B., Rubin, M. A., Rubin, B. P. 2011; 3 (98)


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.

View details for DOI 10.1126/scitranslmed.3002409

View details for Web of Science ID 000294462100004

View details for PubMedID 21885404