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Open Access 01-03-2021 | Glioma | Original Article

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

Authors: Simone Minasi, Caterina Baldi, Francesca Gianno, Manila Antonelli, Anna Maria Buccoliero, Torsten Pietsch, Maura Massimino, Francesca Romana Buttarelli

Published in: Child's Nervous System | Issue 3/2021

Abstract

Purpose

The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined.

Methods

We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR.

Results

Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length.

Conclusion

Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.

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Title: Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma
Authors: Simone Minasi
Caterina Baldi
Francesca Gianno
Manila Antonelli
Anna Maria Buccoliero
Torsten Pietsch
Maura Massimino
Francesca Romana Buttarelli
Publication date: 01-03-2021
Publisher: Springer Berlin Heidelberg
Keywords: Glioma
Glioma
Glioma
Published in: Child's Nervous System / Issue 3/2021
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-020-04933-8

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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