Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer Subtypes

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.

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

“…37 In contrast to a previous study which showed two of six epithelioid sarcomas were alternative lengthening of telomeres positive, 24 all tumors in our series were alternative lengthening of telomeres-negative and ATRX-proficient. Our results suggest that epithelioid sarcomas might be more similar to fusion-associated sarcomas and gastrointestinal stromal tumors, in which a dominant genetic change drives the tumor formation, and alternative lengthening of telomeres does not play important roles in the pathogenesis.…”

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

“…The remaining 10 to 15 % of human cancers do not have detectable telomerase activity, and a subset of such cases maintain telomere length relying on the ALT mechanism [21]. Heaphy and colleagues performed a comprehensive survey on ALT phenotype in 6,110 primary tumours from 94 different cancer subtypes and observed the presence of ALT in 3.7 % of all tumour specimens but its absence in all benign neoplasms and normal tissues [46]. In this study, the ALT phenotype was identified for the first time in medulloblastoma, oligodendroglioma, schwannoma and glioblastoma [46].…”

“…Heaphy and colleagues performed a comprehensive survey on ALT phenotype in 6,110 primary tumours from 94 different cancer subtypes and observed the presence of ALT in 3.7 % of all tumour specimens but its absence in all benign neoplasms and normal tissues [46]. In this study, the ALT phenotype was identified for the first time in medulloblastoma, oligodendroglioma, schwannoma and glioblastoma [46]. Later on, Heaphy and colleagues demonstrated that ATRX or DAXX mutations are closely associated with the development of ALT in pancreatic endocrine tumours whereas ATRX mutations lead to ALT phenotype in cancers of the central nervous system [45].…”

“…In order to evaluate the two aforementioned features, several methods and approaches to measure telomere length, telomerase messenger RNA (mRNA) expression and telomerase enzymatic activity have been developed [113]. Herein, we merely provide a summary of the methods available; for a more detailed review, the reader is referred to references [46] and [115]. The traditional telomere restriction fragment (TRF) analysis measures the average length of all telomeres present in a cell population and is the most used technique for evaluating telomere length [4].…”

The genetic classification of pancreatic neoplasia

“…PanNETs with DAXX/ATRX mutations almost always have the ''alternative lengthening of telomeres'' (ALT?) phenotype [133,134]. Other genes targeted in PanNETs include genes coding for members of the phosphatidylinositol 3 0 -kinase (PI3K)-AKT-mTOR pathway.…”