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

Christopher M. Heaphy, 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. RodenPedram Argani, Angelo M. De Marzo, Luigi Terracciano, Michael Torbenson, Alan K. Meeker

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249 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1608-1615
Number of pages8
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
StatePublished - Oct 1 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Heaphy, C. M., Subhawong, A. P., Hong, S. M., Goggins, M. G., Montgomery, E. A., Gabrielson, E., Netto, G. J., Epstein, J. I., Lotan, T. L., Westra, W. H., Shih, I. M., Iacobuzio-Donahue, C. A., Maitra, A., Li, Q. K., Eberhart, C. G., Taube, J. M., Rakheja, D., Kurman, R. J., Wu, T. C., ... Meeker, A. K. (2011). Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. American Journal of Pathology, 179(4), 1608-1615. https://doi.org/10.1016/j.ajpath.2011.06.018