Article

Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma.

Department of Molecular Genetics and Anatomic Pathology, Lerner Research Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Science translational medicine (Impact Factor: 10.76). 08/2011; 3(98):98ra82. DOI: 10.1126/scitranslmed.3002409
Source: PubMed

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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    ABSTRACT: Objective: Epithelioid hemangioendothelioma is a rare member of vascular tumors of intermediate malignancy. Recently, presence of t(1;3) translocation and WWTR1/CAMTA1 gene fusion, which enhances CAMTA1 expression, are found to be specific to this tumor. We investigated the CAMTA1 immune expression profile of epithelioid hemangioendothelioma and its potential mimickers using a commercially available CAMTA1 antibody. Material and Method: Standard whole sections from the formalin fixed, paraffin embedded blocks of 12 epithelioid hemangioendotheliomas, 10 angiosarcomas, 9 epithelioid sarcomas, 8 malignant melanomas, 8 signet ring carcinomas, 7 lobular carcinomas of breast, 2 epithelioid mesotheliomas, 2 rhabdoid tumors and 12 miscellaneous hemangiomas were immunostained for anti-CAMTA1 (ab64119, 1:200; Abcam) after pretreatment with citrate pH 6.0 for 20 minutes using Leica Bond detection kit with DAB chromogen. Strong nuclear CAMTA1 expression was scored for its extent as 'negative' ( < 5% positive), '+1' (5-25% positive), '2+' (25-50% positive) and '3+' ( > 50% positive). Results: In 60 out of 70 cases (86%) either 2+ or 3+ strong nuclear staining was seen. Eighty-three % of epithelioid hemangioendotheliomas, 100% of angiosarcomas, 89% of epithelioid sarcomas, 89% of malignant melanomas, 63% of signet ring carcinomas, 71% of lobular carcinomas of breast, 100% of epithelioid mesotheliomas, 50% of rhabdoid tumors and 100% of hemangiomas were stained. Besides neurons, CAMTA1 expression was also observed in squamous epithelium, skin adnexa, breast lobules, prostate glands, bile ducts, colonic mucosa and gastric pits. Conclusion: Epithelioid hemangioendothelioma, its potential morphological mimickers and other benign or malignant vascular tumors showed strong and diffuse CAMTA1 expression, nullifying the potential use of CAMTA1 immunohistochemistry as an adjunct in the differential diagnosis.
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    ABSTRACT: Epithelioid hemangioendothelioma is a malignant, often indolent vascular tumor which occurs at various anatomic sites. Based on a reciprocal translocation t (1;3) (p36;q25), a consistent WWTR1-CAMTA1 fusion gene has been found. An alternate YAP1-TFE3 fusion has been detected in a small and distinct subset of cases.
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    ABSTRACT: The aim of this study is to analyse the computed tomographic (CT) findings of pulmonary epithelioid haemangioendothelioma (EHE). The CT features and clinical presentations of six patients (five women, one man; mean age, 53 years) with pathology-proven pulmonary EHE were reviewed. Noncontrast CT images were available for three patients and enhanced CT images for three patients. The image characteristics included the number of tumours, tumour location and size, tumour margins, the presence of calcification/necrosis/cavity, the presence of perivascular location, the presence of pleural lesions, tumour homogeneity at contrast-enhanced CT, tumour enhancement relative to the adjacent muscle and the presence of extrapulmonary lesions. Multiple nodules/masses with irregular margin were shown in all cases, and reticulonodular opacities and ground-glass opacities were found in one case. Overall, the six cases showed 178 nodules/masses, 90 % (160/178) of which were <1 cm in diameter. The average size of the largest nodules/masses in each case was 2.7 cm. The nodules/masses were mostly (93 %, 166/178) located in the subpleural region (<2 cm from the pleura). A total of 48 % (86/178) of nodules/masses showed punctate calcification in four of six cases. All nodules/masses showed perivascular location. Pleural indentation was shown in all cases, as well as pleural-thickening in five cases and pleural effusion in two cases. On contrast-enhanced CT, EHE showed a mildly heterogeneous hyperdense appearance. With predilection for subpleural and perivascular location, typical pulmonary EHE appears as multiple irregular nodules with punctate calcification and pleural indentation.
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