The CDKN2A G500 Allele Is More Frequent in GBM Patients with No Defined Telomere Maintenance Mechanism Tumors and Is Associated with Poorer Survival

Royds, Janice A.; Nadaf, Shafagh Al; Wiles, Anna; Chen, Yu-Jen; Ahn, Antonio; Shaw, Alisha; Bowie, Sara; Lam, Frederic; Baguley, Bruce C.; Braithwaite, Antony W.; MacFarlane, Martin R.; Hung, Noelyn; Slatter, Tania L.

doi:10.1371/journal.pone.0026737

Cited by 28 publications

(45 citation statements)

References 52 publications

(72 reference statements)

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“…4,9 Briefly the promyelocytic leukemia protein was detected using a goat antipromyelocytic leukemia antibody (N-19; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and telomere DNA was detected by fluorescence in situ hybridization with a Cy3-labeled PNA probe (Applied Biosystems, Framingham, MA, USA). Cellular nuclei were stained using 4,6-diamidino-2-phenylindole.…”

Section: Alternative Lengthening Of Telomeres-associated Promyelocytimentioning

confidence: 99%

“…Approximately 34-47% of glioblastoma maintain telomere lengths using telomerase activity. [2][3][4] Telomerase inhibitors decrease glioma cell growth in vitro and in xenograft models, suggesting telomerase inhibitors may work in a clinical setting. 5,6 The alternative lengthening of telomeres method also maintains telomeres and is found in approximately 11-25% of glioblastoma.…”

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confidence: 99%

“…12 Tumors that are alternative lengthening of telomeres positive are associated with isocitrate dehydrogenase 1 (IDH1) and tumor protein 53 (TP53) mutations, a younger age, and secondary glioblastoma suggesting these tumors fit into the gene expression-based proneural subtype. [2][3][4][12][13][14][15] For a large proportion of glioblastomas (40%) the telomere maintenance mechanism is not known and they have been categorized as having a non-defined telomere maintenance mechanism. 3,4 It is possible that these tumors do not activate a telomere maintenance mechanism similar to low-grade astrocytomas, 16,17 or that their telomere maintenance mechanism remains undescribed.…”

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confidence: 99%

“…[2][3][4][12][13][14][15] For a large proportion of glioblastomas (40%) the telomere maintenance mechanism is not known and they have been categorized as having a non-defined telomere maintenance mechanism. 3,4 It is possible that these tumors do not activate a telomere maintenance mechanism similar to low-grade astrocytomas, 16,17 or that their telomere maintenance mechanism remains undescribed. [18][19][20] Another possibility is that non-defined telomere maintenance mechanism tumors are comprised of telomerase and alternative lengthening of telomere-positive tumors, but complications in assaying telomerase activity and measuring the hallmarks of the alternative lengthening of telomeres mechanism lead to falsenegative results.…”

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confidence: 99%

“…29 Telomerase and non-defined telomere maintenance mechanism tumors share other similarities including a similar median patient age, similar overall survival that is poorer compared with alternative lengthening of telomere-positive tumors and infrequent TP53 and IDH1 mutations. [2][3][4] Investigated as a single group of non-alternative lengthening of telomeres tumors, non-defined telomere maintenance mechanism and telomerase-positive tumors responded to temozolomide. 12 If non-defined telomere maintenance mechanism tumors are similar to telomerasepositive tumors they may respond to similar therapies such as telomerase inhibitors.…”

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Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

et al. 2016

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Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor-associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumorassociated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P = 0.0004, and telomerase with and without macrophages P = 0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1-3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs 476% for all other subtypes, P = 0.014). In summary, different immune signatures are found among telomere maintenance mechanism-based subgroups in glioblastoma. The reduced extent of surgical resection of telomerase-positive tumors with macrophages suggests that some tumor-associated macrophages are more unfavorable.

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Section: Alternative Lengthening Of Telomeres-associated Promyelocytimentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

et al. 2016

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Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma

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Hsia

Samaranayaka

et al. 2015

The Journal of Pathology CR

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Uterine smooth muscle tumours of uncertain malignant potential (STUMP) are diagnostically and clinically challenging. The alternative lengthening of telomeres (ALT) telomere maintenance mechanism is associated with poor survival in soft tissue leiomyosarcoma. Time to first recurrence and survival were known for 18 STUMP and 43 leiomyosarcomata (LMS). These were screened for ALT telomere maintenance by the presence of ALT‐associated PML bodies (APBs) and for changes associated with the ALT phenotype, namely aberrant p53 expression, isocitrate dehydrogenase 1 mutation (R132H substitution) expression, mutant ATRX (αthalassemia/mental retardation syndrome X‐linked) expression and mutant DAXX (death‐domain‐associated protein) expression by immunohistochemistry (IHC). Overexpression of p16INK4A was examined immunohistologically in a subset of cases. Many of the tumours associated with death or recurrence demonstrated APBs commensurate with ALT telomere maintenance. However, all uterine STUMP (4/4), and vaginal STUMP (2/2) patients, and almost all LMS patients (88.4%, 23/26, including 90% (9/10) of stage 1 LMS cases), who had died of disease or who had recurrent disease, displayed loss of ATRX or DAXX expression. Loss of ATRX or DAXX expression identified poor prognosis (95% CI 2.1 to 40.8, p < 0.003), in the LMS group. Thus, loss of ATRX or DAXX expression in uterine smooth muscle tumours identifies a clinically aggressive molecular subtype of early stage LMS and when histopathological features are problematic such as in STUMP. As ATRX and DAXX IHC is readily performed in diagnostic laboratories these are potentially useful for routine histopathological classification and management.

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The functional Aquaporin 1 −783G/C-polymorphism is associated with survival in patients with glioblastoma multiforme

et al. 2013

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The CDKN2A G500 Allele Is More Frequent in GBM Patients with No Defined Telomere Maintenance Mechanism Tumors and Is Associated with Poorer Survival

Cited by 28 publications

References 52 publications

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma

The functional Aquaporin 1 −783G/C-polymorphism is associated with survival in patients with glioblastoma multiforme

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