Title | Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Tanas MR, Sboner A, Oliveira AM, Erickson-Johnson MR, Hespelt J, Hanwright PJ, Flanagan J, Luo Y, Fenwick K, Natrajan R, Mitsopoulos C, Zvelebil M, Hoch BL, Weiss SW, Debiec-Rychter M, Sciot R, West RB, Lazar AJ, Ashworth A, Reis-Filho JS, Lord CJ, Gerstein MB, Rubin MA, Rubin BP |
Journal | Sci Transl Med |
Volume | 3 |
Issue | 98 |
Pagination | 98ra82 |
Date Published | 2011 Aug 31 |
ISSN | 1946-6242 |
Keywords | Calcium-Binding Proteins, Chromosome Breakage, Cytogenetic Analysis, Gene Expression Profiling, Gene Fusion, Genome, Human, Hemangioendothelioma, Epithelioid, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Intracellular Signaling Peptides and Proteins, Polymerase Chain Reaction, Trans-Activators, Transcription Factors |
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. |
DOI | 10.1126/scitranslmed.3002409 |
Alternate Journal | Sci Transl Med |
PubMed ID | 21885404 |
Grant List | BREAST CANCER NOW RESEARCH CENTRE / BBC_ / Breast Cancer Now / United Kingdom UL1 RR024989 / RR / NCRR NIH HHS / United States |
Related Faculty:
Andrea Sboner, Ph.D.