Tabori Uri, Vukovic Bisera, Zielenska Maria, Hawkins Cynthia, Braude Ilan, Rutka James, Bouffet Eric, Squire Jeremy, Malkin David
Division of Hematology/Oncology, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
Neoplasia. 2006 Feb;8(2):136-42. doi: 10.1593/neo.05715.
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.
小儿低级别胶质瘤（PLGG）的自发肿瘤消退。我们推测端粒维持功能的缺失是导致这种现象的原因。我们首先在56例PLGG中寻找端粒酶活性和端粒替代延长（ALT）的证据。在11例PLGG中，有0例观察到端粒酶活性，相比之下，13例小儿高级别脑肿瘤中有10例观察到端粒酶活性。45个样本中有45个未检测到ALT。然后，我们对8例惰性PLGG患者进行了Q-FISH检测，这些患者在数年的间隔期内接受了两次异时活检。在所有肿瘤的第二次活检中均观察到端粒缩短，但在正常脑对照中未观察到（P <.0001），这表明端粒维持功能的缺失与端粒的持续侵蚀有关。基于这些观察结果，我们发现表现出更具侵袭性且频繁复发肿瘤的年轻PLGG患者的端粒明显长于年长患者（P =.00014）。末端限制片段长度<7.5的肿瘤未复发，而端粒较长（>8.0）的肿瘤在PLGG中晚期复发的可能性很高。我们的研究结果提供了一种合理的生物学机制来解释PLGG出现生长停滞和自发消退的倾向。因此，端粒维持功能可能是PLGG中首个已知的生物学预后标志物。
