Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas.
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.
Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
Kathleen
K
Dorris
Matthew
M
Sobo
Arzu
A
Onar-Thomas
Eshini
E
Panditharatna
Charles B
CB
Stevenson
Sharon L
SL
Gardner
Mariko D
MD
Dewire
Christopher R
CR
Pierson
Randal
R
Olshefski
Sandra A
SA
Rempel
Stewart
S
Goldman
Lili
L
Miles
Maryam
M
Fouladi
Rachid
R
Drissi
D000293:Adolescent; D001254:Astrocytoma / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D001932:Brain Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D020295:Brain Stem Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D060787:Neoplasm Grading; D011379:Prognosis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000201:enzymology / Q000378:metabolism*; D055815:Young Adult
D012333:RNA, Messenger; C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase