The Role of Telomere Maintenance in the Spontaneous Growth Arrest of Pediatric Low-Grade Gliomas

Abstract

Spontaneous tumor regression of pediatric low-grade gliomas (PLGG). We speculated that lack of telomere maintenance is responsible for this behavior. We first looked for evidence of telomerase activity and alternative lengthening of telomeres (ALT) in 56 PLGG. Telomerase activity was observed in 0 of 11 PLGG, in contrast to 10 of 13 high-grade pediatric brain tumors. There was no ALT in 45 of 45 samples. We then applied Q-FISH to eight patients whose indolent PLGG underwent two metachronous biopsies over a lag of several years. Telomere shortening was observed in the second biopsy in all tumors, but not in normal brain control (P < .0001), indicating that lack of telomere maintenance is associated with continuous telomere erosion. Based on these observations, we found that younger PLGG patients, who exhibit more aggressive and frequently recurrent tumors, had significantly longer telomeres than older ones (P = .00014). Tumors with a terminal restriction fragment length <7.5 did not recur, whereas the presence of longer telomeres (>8.0) conferred a high likelihood of late recurrences in PLGG. Our findings provide a plausible biologic mechanism to explain the tendency of PLGG to exhibit growth arrest and spontaneous regression. Telomere maintenance may therefore represent the first known biologic prognostic marker in PLGG.

Pediatric Ependymoma: Biological Perspectives

“…However, the need to identify new correlates of outcome in pediatric ependymoma has intensified because tumor recurrence can occur in up to 50% of children, despite complete surgical resection and adjuvant radiotherapy, with only approximately 15% of patients subsequently surviving beyond 5 years (2,14,15,21).…”

“…However, only a few of these candidates have been analyzed in sufficient numbers of childhood ependymoma to allow consideration as prognostic markers in this age group. These include human telomerase reverse transcriptase (hTERT) and its nuclear chaperone Nucleolin (15,32), members of the receptor tyrosine kinase 1 (RTK1) family and the Ki-67 labeling index (107,110). Telomerase functions as a homodimer and contains a catalytic component with reverse transcriptase activity (hTERT), which plausibly contributes to pediatric tumor development through failure of hTERT to be transcriptionally repressed (130).…”

“…Telomerase functions as a homodimer and contains a catalytic component with reverse transcriptase activity (hTERT), which plausibly contributes to pediatric tumor development through failure of hTERT to be transcriptionally repressed (130). Characteristic features of neoplastic cells include the capacity for unlimited proliferation and the ability to avoid senescence, both of which require maintenance of telomere length (15). Telomeres are protective nucleoprotein structures that cap human chromosomal termini and contribute to genomic stability (131,132).…”

“…In addition, late relapses up to 15 years after initial treatment are not uncommon (13). The ability to predict patient outcome has been hampered by the heterogeneous clinical behavior of ependymomas in children, insufficient recruitment into large prospective clinical trials, and contradictory studies of existing clinicopathological prognostic markers (14,15).…”

“…However, although complete resection is the most consistently reported favorable clinical prognostic factor (1,(16)(17)(18), this is not a universal finding and some studies fail to show this relationship for pediatric posterior fossa tumors (19,20). Furthermore, despite complete excision, local tumor recurrence can develop in up to 50% of cases, even following adjuvant radiotherapy (14,15,21).…”