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Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes
Authors:Heaphy Christopher M  Subhawong Andrea P  Hong Seung-Mo  Goggins Michael G  Montgomery Elizabeth A  Gabrielson Edward  Netto George J  Epstein Jonathan I  Lotan Tamara L  Westra William H  Shih Ie-Ming  Iacobuzio-Donahue Christine A  Maitra Anirban  Li Qing K  Eberhart Charles G  Taube Janis M  Rakheja Dinesh  Kurman Robert J  Wu T C  Roden Richard B  Argani Pedram  De Marzo Angelo M  Terracciano Luigi  Torbenson Michael  Meeker Alan K
Affiliation:Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ameeker1@jhmi.edu
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.
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