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. 2006 Feb;8(2):136-42.
doi: 10.1593/neo.05715.

The role of telomere maintenance in the spontaneous growth arrest of pediatric low-grade gliomas

Uri Tabori  1 , Bisera Vukovic, Maria Zielenska, Cynthia Hawkins, Ilan Braude, James Rutka, Eric Bouffet, Jeremy Squire, David Malkin
Affiliations

The role of telomere maintenance in the spontaneous growth arrest of pediatric low-grade gliomas

Uri Tabori et al. Neoplasia. 2006 Feb.

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.

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Figures

Figure 1
Figure 1
Q-FISH images from two sequential biopsies of a patient with a pilocytic astrocytoma. FISH with centromeric (FITC; green) and telomeric (Cy3; red) PNA probes on paraffin-embedded recurrent PLGG. DAPI was used as a counterstain with x 100 (left) and x 10 (middle) objectives. Identical images in black and white (right) with nuclei outlined in gray and telomere signals represented by dark spots. Red dots represent telomeres, and green dots represent centromeres.
Figure 2
Figure 2
Q-FISH analysis of telomere length. The y-axis represents telomere divided by centromere fluorescent intensity. Telomere intensity was reduced in the second surgery as compared to the first surgery in all patients, but not in the normal brain control. P value was calculated for 30 cells from the first tumor biopsy compared with the same number from the second tumor biopsy, per patient.
Figure 3
Figure 3
TRF measurement for subgroups of PLGG patients. (A) Mean TRF length in patients younger than 4 years (n = 12) and older than 10 years (n = 13). (B) TRF analysis of PLGG in younger and older patients. Note the longer mean TRF for younger patients.
Figure 4
Figure 4
Time to last progression as a function of TRF length. Patients who did not progress were designated as time to last progression = 0.
See this image and copyright information in PMC

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