Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes - PubMed (original) (raw)

. 2011 Oct;179(4):1608-15.

doi: 10.1016/j.ajpath.2011.06.018. Epub 2011 Sep 1.

Andrea P Subhawong, Seung-Mo Hong, Michael G Goggins, Elizabeth A Montgomery, Edward Gabrielson, George J Netto, Jonathan I Epstein, Tamara L Lotan, William H Westra, Ie-Ming Shih, Christine A Iacobuzio-Donahue, Anirban Maitra, Qing K Li, Charles G Eberhart, Janis M Taube, Dinesh Rakheja, Robert J Kurman, T C Wu, Richard B Roden, Pedram Argani, Angelo M De Marzo, Luigi Terracciano, Michael Torbenson, Alan K Meeker

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Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes

Christopher M Heaphy et al. Am J Pathol. 2011 Oct.

Abstract

Approximately 10% to 15% of human cancers lack detectable telomerase activity, and a subset of these maintain telomere lengths by the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in subtypes of sarcomas and astrocytomas, has rarely been reported in epithelial malignancies. However, the prevalence of ALT has not been thoroughly assessed across all cancer types. We therefore comprehensively surveyed the ALT phenotype in a broad range of human cancers. In total, two independent sets comprising 6110 primary tumors from 94 different cancer subtypes, 541 benign neoplasms, and 264 normal tissue samples were assessed by combined telomere-specific fluorescence in situ hybridization and immunofluorescence labeling for PML protein. Overall, ALT was observed in 3.73% (228/6110) of all tumor specimens, but was not observed in benign neoplasms or normal tissues. This is the first report of ALT in carcinomas arising from the bladder, cervix, endometrium, esophagus, gallbladder, kidney, liver, and lung. Additionally, this is the first report of ALT in medulloblastomas, oligodendrogliomas, meningiomas, schwannomas, and pediatric glioblastoma multiformes. Previous studies have shown associations between ALT status and prognosis in some tumor types; thus, further studies are warranted to assess the potential prognostic significance and unique biology of ALT-positive tumors. These findings may have therapeutic consequences, because ALT-positive cancers are predicted to be resistant to anti-telomerase therapies.

Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1

Representative examples of ALT-negative and ALT-positive tumors. A and B: Representative invasive urothelial carcinomas. In the ALT-negative case (A), robust telomere signals are present in tumor cells and adjacent stromal cells (asterisks). In the ALT-positive case (B), distinctive large, very bright intranuclear foci of telomere FISH signals mark ALT-associated telomeric foci throughout the tumor cells (arrows). Note the marked heterogeneity in the telomere signals, where visible, in the cancer cells. C–F: Representative ALT-positive cases of renal sarcomatoid carcinoma (C), anaplastic medulloblastoma (D), oligodendroglioma (E), and angiosarcoma (F). In all images (A–F), the DNA is stained with DAPI (blue) and telomere DNA is stained with the Cy3-labeled telomere-specific PNA probe (red). Two cases (E and F) are shown with costaining of PML protein (green), to demonstrate colocalization to most of the ALT-associated telomeric foci (arrows). The inset for each case highlights a typical APB that contains a targetoid appearance of telomere signal with a peripheral rim of PML protein. Original magnification: ×400 (A–F); ×1000 (inset).

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