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A Robust Assay for Alternative Lengthening of Telomeres in Tumors Shows the Significance of Alternative Lengthening of Telomeres in Sarcomas and Astrocytomas

¹ Children's Medical Research Institute; ² Royal Prince Alfred Hospital; ³ Children's Hospital Westmead; ⁴ Royal North Shore Hospital, University of Sydney; and ⁵ Douglass Hanly Moir Pathology, Sydney, New South Wales, Australia; ⁶ MD Anderson Cancer Center, Houston, Texas; ⁷ University of Otago, Dunedin, New Zealand; ⁸ Royal Hallamshire Hospital, Sheffield, United Kingdom; ⁹ University of Iowa, Iowa City, Iowa; and ¹⁰ Department of Pathology, St Vincent's Hospital, Catholic University, Suwon, Kyungkido, South Korea

Requests for reprints: Roger Reddel, Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, New South Wales 2145, Australia. Phone: 61-2-96872800; Fax: 612-968-72120; E-mail:rreddel{at}cmri.usyd.edu.au.

Purpose and Experimental Design: Telomeres of tumor cells may be maintained by telomerase or by alternative lengthening of telomeres (ALT). The standard ALT assay requires Southern analysis of high molecular weight genomic DNA. We aimed to establish and validate an ALT assay suitable for archived paraffin-embedded tumors and to use it to examine the prevalence and clinical significance of ALT in various types of tumors that are often telomerase negative.

Results: To assay for ALT, we detected ALT-associated promyelocytic leukemia (PML) bodies (APBs) by combined PML immunofluorescence and telomere fluorescence in situ hybridization. APBs are PML nuclear domains containing telomeric DNA and are a known hallmark of ALT in cell lines. The APB assay concurred with the standard ALT assay in 62 of 62 tumors and showed that 35% of 101 soft tissue sarcomas (STS), 47% of 58 osteosarcomas (especially younger patients), 34% of 50 astrocytomas, and 0% of 17 papillary thyroid carcinomas were ALT positive (ALT+). The prevalence of ALT varied greatly among different STS subtypes: malignant fibrous histiocytomas, 77%; leiomyosarcomas, 62%; liposarcomas, 33%; synovial sarcomas, 9%; and rhabdomyosarcomas, 6%. ALT correlated with survival in glioblastoma multiforme and occurred more often in lower-grade astrocytomas, but ALT+ and ALT– sarcomas were equally aggressive in terms of grade and clinical outcome.

Conclusion: The APB assay for ALT is suitable for paraffin-embedded tumors. It showed that a substantial proportion of STS, osteosarcomas, and astrocytomas, but not papillary thyroid carcinomas use ALT. APB positivity correlated strongly with survival of patients with astrocytomas.

Key Words: ALT-associated PML body • soft tissue sarcoma • osteosarcoma • glioblastoma multiforme • papillary carcinoma of thyroid

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