Dorris Kathleen, Sobo Matthew, Onar-Thomas Arzu, Panditharatna Eshini, Stevenson Charles B, Gardner Sharon L, Dewire Mariko D, Pierson Christopher R, Olshefski Randal, Rempel Sandra A, Goldman Stewart, Miles Lili, Fouladi Maryam, Drissi Rachid
Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
J Neurooncol. 2014 Mar;117(1):67-76. doi: 10.1007/s11060-014-1374-9. Epub 2014 Jan 30.
Children with high-grade glioma, including diffuse intrinsic pontine glioma (DIPG), have a poor prognosis despite multimodal therapy. Identifying novel therapeutic targets is critical to improve their outcome. We evaluated prognostic roles of telomere maintenance mechanisms in children with HGG, including DIPG. A multi-institutional retrospective study was conducted involving 50 flash-frozen HGG (35 non-brainstem; 15 DIPG) tumors from 45 children (30 non-brainstem; 15 DIPG). Telomerase activity, expression of hTERT mRNA (encoding telomerase catalytic component) and TERC (telomerase RNA template) and alternative lengthening of telomeres (ALT) mechanism were assayed. Cox Proportional Hazard regression analyses assessed association of clinical and pathological variables, TERC and hTERT levels, telomerase activity, and ALT use with progression-free or overall survival (OS). High TERC and hTERT expression was detected in 13/28 non-brainstem HGG samples as compared to non-neoplastic controls. High TERC and hTERT expression was identified in 13/15 and 11/15 DIPG samples, respectively, compared to controls. Evidence of ALT was noted in 3/11 DIPG and 10/19 non-brainstem HGG specimens. ALT and telomerase use were identified in 4/19 non-brainstem HGG and 2/11 DIPG specimens. In multivariable analyses, increased TERC and hTERT levels were associated with worse OS in patients with non-brainstem HGG, after controlling for tumor grade or resection extent. Children with HGG and DIPG, have increased hTERT and TERC expression. In children with non-brainstem HGG, increased TERC and hTERT expression levels are associated with a worse OS, making telomerase a promising potential therapeutic target in pediatric HGG.
患有高级别胶质瘤的儿童，包括弥漫性脑桥内在胶质瘤（DIPG），尽管接受了多模式治疗，预后仍然很差。确定新的治疗靶点对于改善他们的预后至关重要。我们评估了端粒维持机制在包括DIPG在内的高级别胶质瘤儿童中的预后作用。进行了一项多机构回顾性研究，纳入了来自45名儿童（30名非脑干胶质瘤；15名DIPG）的50个速冻高级别胶质瘤肿瘤（35个非脑干肿瘤；15个DIPG肿瘤）。检测了端粒酶活性、hTERT mRNA（编码端粒酶催化成分）和TERC（端粒酶RNA模板）的表达以及端粒的替代延长（ALT）机制。Cox比例风险回归分析评估了临床和病理变量、TERC和hTERT水平、端粒酶活性以及ALT的使用与无进展生存期或总生存期（OS）之间的关联。与非肿瘤对照相比，在13/28个非脑干高级别胶质瘤样本中检测到TERC和hTERT高表达。与对照相比，分别在13/15个和11/15个DIPG样本中鉴定出TERC和hTERT高表达。在3/11个DIPG和10/19个非脑干高级别胶质瘤标本中发现了ALT的证据。在4/19个非脑干高级别胶质瘤和2/11个DIPG标本中鉴定出ALT和端粒酶的使用。在多变量分析中，在控制肿瘤分级或切除范围后，TERC和hTERT水平升高与非脑干高级别胶质瘤患者较差的总生存期相关。患有高级别胶质瘤和DIPG的儿童，hTERT和TERC表达增加。在非脑干高级别胶质瘤儿童中，TERC和hTERT表达水平升高与较差的总生存期相关，这使得端粒酶成为小儿高级别胶质瘤中一个有前景的潜在治疗靶点。
