Association of MutantTP53with Alternative Lengthening of Telomeres and Favorable Prognosis in Glioma

Abstract

The molecular basis for alternative lengthening of telomeres (ALT), a prognostic marker for glioma patients, remains unknown. We examined TP53 status in relation to telomere maintenance mechanism (TMM) in 108 patients with glioblastoma multiforme and two patients with anaplastic astrocytoma from New Zealand and United Kingdom. Tumor samples were analyzed with respect to telomerase activity, telomere length, and ALT-associated promyelocytic leukemia nuclear bodies to determine their TMM. TP53 mutation was analyzed by direct sequencing of coding exons 2 to 11. We found an association between TP53 mutation and ALT mechanism and between wild-type TP53 and telomerase and absence of a known TMM (P < 0.0001). We suggest that TP53 deficiency plays a permissive role in the activation of ALT.

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

“…16 In addition, non-defined telomere maintenance mechanism tumors with TP53 mutations showed a trend toward increased patient survival. 2 Improved patient survival associated with TP53 mutations was found for alternative lengthening of telomeres tumors, but TP53 mutations in telomerasepositive tumors were associated with poor patient survival. 2 In combination with RNA-Seq we report that glioblastomas with a non-defined telomere maintenance mechanism are comprised of three distinct subgroups, each with a poor patient prognosis.…”

“…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.…”

“…5,6 The alternative lengthening of telomeres method also maintains telomeres and is found in approximately 11-25% of glioblastoma. 2,3,7 Although the exact mechanism that gives rise to alternative lengthening of telomeres is unknown, distinguishing features are long and heterogeneous telomere lengths, and nuclear co-localizations of telomere DNA and the promyelocytic leukemia protein called alternative lengthening of telomere-associated promyelocytic leukemia bodies. [8][9][10][11] Alternative lengthening of telomere-positive tumors are associated with an improved patient survival, despite alternative lengthening of telomere-positive tumors responding poorly to adjuvant therapy.…”

“…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.…”

“…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.…”