Research ArticlesCancer

Identification of a Disease-Defining Gene Fusion in Epithelioid Hemangioendothelioma

Science Translational Medicine  31 Aug 2011:
Vol. 3, Issue 98, pp. 98ra82
DOI: 10.1126/scitranslmed.3002409

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FISHing for a Gene Fusion

Mother was right: There is a time and place for everything. And at the molecular level, inappropriate behavior can have consequences much more severe than being grounded. Using an unbiased deep-sequencing approach coupled with traditional chromosomal karyotyping, Tanas et al. now describe the genes involved in a fusion event that defines epithelioid hemangioendothelioma (EHE), a rare vascular cancer. This genetic aberration may instigate the bad behavior—an improper transcriptional program in endothelial cells.

A rare sarcoma, EHE is difficult to diagnose because it shares many characteristics with normal endothelial cells and resembles other abnormal vascular neoplasms, such as epithelioid hemangioma, a benign condition, and epithelioid angiosarcoma, an aggressive vascular cancer. Treatment for patients with localized EHE includes surgical removal, when possible, or liver transplantation in the case of hepatic involvement, and there is no treatment for metastatic disease. To aid in diagnosis and decipher the pathological processes behind this mysterious cancer, researchers and clinicians need a defining biomarker for EHE.

Traditional cytogenetic techniques for identifying the genes involved in a genetic translocation are labor-intensive, especially for a rare cancer for which no cell lines are available. So, Tanas et al. took a shortcut; the authors combined cytogenetic methods with deep transcriptome sequencing, which they used to search in an unbiased way for the product of the t(1;3)(p36;q25) chromosomal translocation characteristic of EHE. The translocation involved two genes, WWTR1, which encodes a transcriptional coactivator that is highly expressed in endothelial cells, and CAMTA1, a DNA binding transcriptional regulatory protein that is normally expressed during brain development. The WWTR1/CAMTA1 gene fusion contains the strong endothelial cell promoter of WWTR1, which may drive the inappropriate expression of a protein-encoding fragment of CAMTA1 in endothelial cells. The authors suggest that this promoter switch initiates an ill-suited and ill-timed transcriptional program that may play a role in cancer biology. If this is the case, then the chimeric WWTR1/CAMTA1 transcription factor may represent a therapeutic target for EHE-specific drugs. To aid in disease diagnosis, Tanas et al. also devised a sensitive and specific fluorescence in situ hybridization assay to detect the EHE translocation. Together, these tools should teach researchers about the biology and prognosis of this rare cancer and eventually help bring the bad behavior under control.


  • Citation: M. R. Tanas, A. Sboner, A. M. Oliveira, M. R. Erickson-Johnson, J. Hespelt, P. J. Hanwright, J. Flanagan, Y. Luo, K. Fenwick, R. Natrajan, C. Mitsopoulos, M. Zvelebil, B. L. Hoch, S. W. Weiss, M. Debiec-Rychter, R. Sciot, R. B. West, A. J. Lazar, A. Ashworth, J. S. Reis-Filho, C. J. Lord, M. B. Gerstein, M. A. Rubin, B. P. Rubin, Identification of a Disease-Defining Gene Fusion in Epithelioid Hemangioendothelioma. Sci. Transl. Med. 3, 98ra82 (2011).