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Journal of Neuro-Oncology

, Volume 142, Issue 3, pp 435–444 | Cite as

Telomere elongation via alternative lengthening of telomeres (ALT) and telomerase activation in primary metastatic medulloblastoma of childhood

  • Simone Minasi
  • Caterina Baldi
  • Torsten Pietsch
  • Vittoria Donofrio
  • Bianca Pollo
  • Manila Antonelli
  • Maura Massimino
  • Felice Giangaspero
  • Francesca Romana ButtarelliEmail author
Laboratory Investigation

Abstract

Purpose

Elongation of telomeres is necessary for tumor cell immortalization and senescence escape; neoplastic cells use to alternative pathways to elongate telomeres: telomerase reactivation or a telomerase-independent mechanism termed alternative lengthening of telomeres (ALT). Telomerase and ALT pathway has been explored in adult and pediatric gliomas and medulloblastomas (MDBs); however, these mechanisms were not previously investigated in MDBs metastatic at the onset. Therefore, we analyzed the activation of telomerase and ALT pathway in a homogenous cohort of 43 pediatric metastatic medulloblastomas, to investigate whether telomere elongation could play a role in the biology of metastatic MDB.

Methods

We evaluated telomeres length via telomere-specific fluorescence in situ hybridization (Telo-FISH); we assessed nuclear expression of ATRX by immunohistochemistry (IHC). H3F3A and TERT promoter mutations were analyzed by pyrosequencing, while UTSS methylation status was analyzed via methylation-specific-PCR (MS-PCR).

Results

H3F3A mutations were absent in all MDBs, 30% of samples showed ATRX nuclear loss, 18.2% of cases were characterized by TERT promoter mutations, while 60.9% harboured TERT promoter hyper-methylation in the UTSS region. Elongation of telomeres was found in 42.8% of cases. Metastatic MDBs control telomere elongation via telomerase activation (10.7%), induced by TERT promoter mutations in association with UTSS hyper-methylation, and ALT mechanism (32.1%), triggered by ATRX inactivation. Among non-metastatic MDBs, only 5.9% (1/17) showed ATRX nuclear loss with activation of ALT.

Conclusions

Our metastatic cases frequently activate ALT pathway, suggesting that it is a common process for senescence escape in primary metastatic medulloblastomas. Furthermore, the activation of mechanisms for telomere elongation is not restricted to certain molecular subgroups in this high-risk group of MDBs.

Keywords

Alternative lengthening of telomeres Telomerase TERT mutations ATRX H3F3A Metastatic medulloblastomas 

Notes

Acknowledgements

Simone Minasi was supported by “Associazione Fabrizio Procaccini Onlus” (Grant No. 121). The study was also supported by “Associazione con Lorenzo per mano” (Grant No. 212).

Compliance with ethical standards

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

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Supplementary material 1 (DOC 1954 KB)
11060_2019_3127_MOESM2_ESM.doc (41 kb)
Supplementary material 2 (DOC 41 KB)
11060_2019_3127_MOESM3_ESM.xls (28 kb)
Supplementary material 3 (XLS 28 KB)
11060_2019_3127_MOESM4_ESM.xls (22 kb)
Supplementary material 4 (XLS 22 KB)

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Authors and Affiliations

  1. 1.Department of Radiological, Oncological and Anatomo-Pathological SciencesSapienza University of RomeRomeItaly
  2. 2.Department of Human NeurosciencesSapienza University of RomeRomeItaly
  3. 3.Pediatric UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanoItaly
  4. 4.Department of Molecular MedicineSapienza University of RomeRomeItaly
  5. 5.IRCCS NeuromedPozzilliItaly
  6. 6.Pathology UnitOspedale Santobono-PausiliponNaplesItaly
  7. 7.Neuropathology UnitIRCCS Istituto Neurologico Carlo BestaMilanoItaly
  8. 8.Institute of Neuropathology, DGNN Brain Tumor Reference CenterUniversity of Bonn Medical CenterBonnGermany

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