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 G34Rmutation, 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 H3.3mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT tomaintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27Mtumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.

Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma / Minasi, Simone; Baldi, Caterina; Gianno, Francesca; Antonelli, Manila; Maria Buccoliero, Anna; Pietsch, Torsten; Massimino, Maura; Buttarelli, Francesca Romana. - In: CHILDS NERVOUS SYSTEM. - ISSN 0256-7040. - 37:3(2021), pp. 809-818. [10.1007/s00381-020-04933-8]

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

Simone Minasi
Co-primo
;
Caterina Baldi
Co-primo
;
Francesca Gianno;Manila Antonelli;Francesca Romana Buttarelli
Ultimo
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 G34Rmutation, 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 H3.3mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT tomaintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27Mtumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.
2021
telomeres; alternative lengthening of telomeres; H3.3; paediatric high grade gliomas
01 Pubblicazione su rivista::01a Articolo in rivista
Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma / Minasi, Simone; Baldi, Caterina; Gianno, Francesca; Antonelli, Manila; Maria Buccoliero, Anna; Pietsch, Torsten; Massimino, Maura; Buttarelli, Francesca Romana. - In: CHILDS NERVOUS SYSTEM. - ISSN 0256-7040. - 37:3(2021), pp. 809-818. [10.1007/s00381-020-04933-8]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1428374
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