Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas
Journal
Human Pathology
Journal Volume
46
Journal Issue
9
Pages
1360-1366
Date Issued
2015
Author(s)
Abstract
Summary 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. ? 2015 Elsevier Inc.
SDGs
Other Subjects
alpha thalassemia mental retardation syndrome X linked protein; death domain associated protein; protein; telomerase reverse transcriptase; unclassified drug; ATRX protein, human; DNA helicase; nuclear protein; telomerase; TERT protein, human; tumor marker; adult; aged; Article; breast cancer; clinical feature; cystosarcoma phylloides; female; fluorescence in situ hybridization; follow up; gene mutation; hemangioendothelioma; hepatic angiosarcoma; histopathology; human; human tissue; Kaposi sarcoma; liver sarcoma; major clinical study; male; malignant peripheral nerve sheath tumor; mitosis rate; nasopharynx carcinoma; phenotype; promoter region; protein expression; survival; telomere homeostasis; undifferentiated carcinoma; uterine cervix carcinoma; vascular tumor; angiosarcoma; down regulation; enzymology; genetics; immunohistochemistry; liver tumor; middle aged; mortality; mutation; nucleotide sequence; pathology; prognosis; skin tumor; telomere; Adult; Aged; DNA Helicases; DNA Mutational Analysis; Down-Regulation; Female; Hemangioendothelioma, Epithelioid; Hemangiosarcoma; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Liver Neoplasms; Male; Middle Aged; Mutation; Nuclear Proteins; Prognosis; Promoter Regions, Genetic; Sarcoma, Kaposi; Skin Neoplasms; Telomerase; Telomere; Telomere Homeostasis; Tumor Markers, Biological
Publisher
W.B. Saunders
Type
journal article