RESUMEN
Pseudomyogenic haemangioendothelioma (PHE) is an intermediate malignant vascular soft tissue tumour primarily affecting children and young adults. The molecular basis of this neoplasm is unknown. We here used chromosome banding analysis, fluorescence in situ hybridization (FISH), mRNA sequencing, RT-PCR and quantitative real-time PCR on a series of morphologically well-characterized PHEs to show that a balanced translocation, t(7;19)(q22;q13), detected as the sole cytogenetic aberration in two cases, results in fusion of the SERPINE1 and FOSB genes. This translocation has not been observed in any other bone or soft tissue tumour. Interphase FISH on sections from eight additional PHEs identified the same SERPINE1-FOSB fusion in all cases. The role of SERPINE1, which is highly expressed in vascular cells, in this gene fusion is probably to provide a strong promoter for FOSB, which was found to be expressed at higher levels in PHEs than in other soft tissue tumours. FOSB encodes a transcription factor belonging to the FOS family of proteins, which, together with members of the JUN family of transcription factors, are major components of the activating protein 1 (AP-1) complex. Further studies are needed to understand the cellular impact of the aberrant expression of the FOSB gene, but as the t(7;19) resulting in the SERPINE1-FOSB fusion seems to be pathognomonic for PHE, FISH or RT-PCR could be useful for differential diagnostic purposes.
Asunto(s)
Neoplasias Óseas/genética , Regulación Neoplásica de la Expresión Génica , Fusión Génica , Hemangioendotelioma Epitelioide/genética , Inhibidor 1 de Activador Plasminogénico/genética , Proteínas Proto-Oncogénicas c-fos/genética , Neoplasias de los Tejidos Blandos/genética , Transcripción Genética , Adolescente , Neoplasias Óseas/enzimología , Neoplasias Óseas/patología , Bandeo Cromosómico , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 7 , Femenino , Pruebas Genéticas/métodos , Hemangioendotelioma Epitelioide/enzimología , Hemangioendotelioma Epitelioide/patología , Humanos , Hibridación Fluorescente in Situ , Masculino , Valor Predictivo de las Pruebas , ARN Mensajero/análisis , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ARN , Neoplasias de los Tejidos Blandos/enzimología , Neoplasias de los Tejidos Blandos/patología , Translocación Genética , Regulación hacia ArribaRESUMEN
Alternative lengthening of telomeres (ALT) is a mechanism using homologous recombination to maintain telomere length and sustain limitless replicability of cancer cells. Recently, ALT has been found to be associated with inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. In this study, 119 tumors (88 angiosarcomas, 11 epithelioid hemangioendotheliomas, and 20 Kaposi sarcomas) were analyzed to determine the ALT status, its relationship to loss of ATRX/DAXX expression, and the clinicopathological features. In addition, the mutation status in the telomerase reverse transcriptase gene (TERT) promoter was also studied. Loss of ATRX expression was observed in 21% (16/77) of the primary angiosarcomas and 9% (1/11) of epithelioid hemangioendotheliomas. DAXX expression was intact in all but 2 ATRX-deficient angiosarcomas. Telomere-specific fluorescence in situ hybridization assay showed 28% (17/61) of the primary angiosarcomas were ALT positive. Remarkably, ALT was highly associated with loss of ATRX expression: all but 2 ALT-positive angiosarcomas were ATRX deficient. Notably, hepatic angiosarcomas were frequently ATRX deficient (8/13) and/or ALT positive (8/12). None of the secondary angiosarcomas were ATRX/DAXX deficient or ALT positive. The only ATRX-deficient epithelioid hemangioendothelioma was positive for ALT. Forty-seven angiosarcomas were tested for TERT promoter mutation. Despite the fact that angiosarcoma occurs most commonly in sun-damaged skin, mutation was detected in only 1 radiation-associated angiosarcoma (2%). We conclude that ALT is an important telomere maintenance mechanism in primary angiosarcomas. This feature is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.
Asunto(s)
Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , ADN Helicasas/análisis , Hemangiosarcoma/enzimología , Hemangiosarcoma/genética , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Proteínas Nucleares/análisis , Homeostasis del Telómero , Telómero/genética , Adulto , Anciano , Análisis Mutacional de ADN , Regulación hacia Abajo , Femenino , Hemangioendotelioma Epitelioide/enzimología , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patología , Hemangiosarcoma/mortalidad , Hemangiosarcoma/patología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Regiones Promotoras Genéticas , Sarcoma de Kaposi/enzimología , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patología , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Telomerasa/genética , Proteína Nuclear Ligada al Cromosoma XRESUMEN
The concentration of group II phospholipase A2 was measured in blood plasma samples before and after liver transplantation in a 27-year-old woman who suffered from a massive epitheloid hemangioendothelioma of the liver. The pretransplantation concentration of group II phospholipase A2 was 830 microg/L, which is markedly above the upper limit of the reference interval (10.8 microg/L). After the transplantation, there was a dramatic decrease in the group II phospholipase A2 level (33 microg/L on the first posttransplantation day). In situ hybridization of mRNA and immunohistochemistry revealed synthesis of group II phospholipase A2 in hepatocytes in non-neoplastic areas of the liver. Tumor cells did not contain group II phospholipase A2. The results indicate that group II phospholipase A2 circulating in blood plasma originates in hepatocytes.