Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme

Hakin-Smith, V.; Jellinek, DA; Levy, David E.; Carroll, Thomas; Teo, Mario; Timperley, WR; McKay, MJ; Reddel, Roger R.; Royds, JA

doi:10.1016/s0140-6736(03)12681-5

Cited by 239 publications

(249 citation statements)

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“…This is the first report of the ALT telomere maintenance mechanism in pediatric GBMs, medulloblastomas, oligodendrogliomas, meningiomas, and schwannomas. The presence of the ALT phenotype in GBM has been described previously, 15,[25][26][27] but all cases assessed were in adults. The prevalence of the ALT phenotype in adult GBM cases in the present study (11%) is similar to that in a recently published large retrospective series using the same assay (15%).…”

Section: Altered Telomere Lengths In Cancer 1613mentioning

confidence: 76%

“…27 Previous studies on smaller sets of adult GBM reported prevalence at 22% (7/32) 15 and 25% (19/77). 26 Notably, Henson et al 15 observed an inverse relationship between ALT-positivity and patient age, and this observation was confirmed by McDonald et al 27 in a retrospective cohort. Here, we report a significantly increased prevalence in pediatric GBM (44%), compared with adult GBM (11%).…”

Section: Altered Telomere Lengths In Cancer 1613mentioning

confidence: 78%

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

Heaphy

Subhawong

Hong

et al. 2011

The American Journal of Pathology

433

455

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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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Section: Altered Telomere Lengths In Cancer 1613mentioning

confidence: 76%

Section: Altered Telomere Lengths In Cancer 1613mentioning

confidence: 78%

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

Heaphy

Subhawong

Hong

et al. 2011

The American Journal of Pathology

433

455

View full text Add to dashboard Cite

show abstract

“…The association of the ALT phenotype with clinical aggressiveness has been shown previously for liposarcoma (Costa et al, 2006); however, the prognostic significance of ALT appears to be tissue and tumour type-specific. In osteosarcoma, hTERT is a predictive indicator of worse prognosis, with a trend in favour of shorter progression-free survival in patients whose tumours expressed telomerase rather than ALT (Sanders et al, 2004), while in glioblastoma multiforme the presence of ALT is actually indicative of a better prognosis (Hakin-Smith et al, 2003). The correlation between TMM, telomerase gene expression and the various tissue-specific clinical outcomes may reflect the underlying complexity of telomere biology in different tumour types and certainly is of great importance to understanding telomere maintenance and telomerase regulation.…”

Section: Discussionmentioning

confidence: 99%

“…In osteosarcoma, telomerase expression is associated with shorter progression-free survival (Sanders et al, 2004), while in liposarcoma the ALT phenotype is associated with a lower survival rate (Costa et al, 2006). This appears to be tissue specific, as the presence of the ALT phenotype in patients with glioblastoma multiforme was associated with a longer survival rate than those with telomerase activity or no TMM (Hakin-Smith et al, 2003).…”

mentioning

confidence: 95%

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

et al. 2008

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Telomere length is maintained by two known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype. We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models. Here, we evaluate these findings and investigate their prognostic significance in a panel of liposarcoma tissue samples to understand the biology underlying the ALT phenotype. Liposarcoma samples were split into three groups: telomerase positive (Tel þ ); ALT positive; ALTÀ/TelÀ. Differences in telomerase gene expression were evident between the groups with increased expression of hTR in ALT and Tel þ compared to ALTÀ/TelÀ samples and increased hTERT in Tel þ samples only. Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression. We confirm that the presence of the ALT phenotype is associated with poor prognosis and in addition, for the first time, we show a direct association between hTR expression and poor prognosis in liposarcoma patients.

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“…29 These findings have important clinical significance, as ALT identifies a sub-type of GBM that has a more favorable prognosis and occurs in younger patients (Figure 1). 30 In a study of 77 GBM patients, it was found that ALT more than doubled the median survival for patients with GBM (542 versus 247 days). 30 In a later study, we showed that TP53 mutations are prognostic only in younger patients (median survival 490 versus 316 days, P ¼ 0.01).…”

Section: Introductionmentioning

confidence: 99%

p53 and disease: when the guardian angel fails

2006

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The p53 tumor suppressor gene (TP53) is mutated more often in human cancers than any other gene yet reported. Of importance, it is mutated frequently in the common human malignancies of the breast and colorectum and also, but less frequently, in other significant human cancers such as glioblastomas. There is also one inherited cancer predisposing syndrome called Li-Fraumeni that is caused by TP53 mutations. In this review, we discuss the significance of p53 mutations in some of the above tumors with a view to outlining how p53 contributes to malignant progression. We also discuss the usefulness of TP53 status as a prognostic marker and its role as a predictor of response to therapy. Finally, we outline some evidence that abnormalities in p53 function contribute to the etiology of other non-neoplastic diseases.

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Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme

Cited by 239 publications

References 5 publications

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

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

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma

p53 and disease: when the guardian angel fails

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