title: Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.
abstract: 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.
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Jau-Yu
authors.initials: JY
authors.lastname: Liau
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Jia-Huei
authors.initials: JH
authors.lastname: Tsai
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei 10002, Taiwan.
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Cher-Wei
authors.initials: CW
authors.lastname: Liang
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Hung-Han
authors.initials: HH
authors.lastname: Hsu
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei 10002, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10051, Taiwan. Electronic address: mrna0912@yahoo.com.tw.
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D004265:DNA Helicases / Q000032:analysis*; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D018323:Hemangioendothelioma, Epithelioid / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006394:Hemangiosarcoma / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012514:Sarcoma, Kaposi / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D059505:Telomere Homeostasis; D000075924:X-linked Nuclear Protein
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; C509186:TERT protein, human; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATRX; Alternative lengthening of telomeres; Angiosarcoma; TERT; Telomere