Alternative lengthening of tetomeres phenotype in malignant vascular tumors is highly associated with toss of ATRX expression and is frequently observed in hepatic angiosarcomas

作者：Liau Jau Yu; Tsai Jia Huei; Yang Ching Yao; Lee Jen Chieh; Liang Cher Wei; Hsu Hung Han; Jeng Yung Ming^*

来源：Human Pathology, 2015, 46(9): 1360-1366.

DOI：10.1016/j.humpath.2015.05.019

• Angiosarcoma
• Telomere
• Alternative lengthening of telomeres
• TERT
• ATRX

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 alpha-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.

• 出版日期2015-9