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H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: possible diagnostic and therapeutic implications?

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Abstract

Pediatric glioblastomas recently have been exon sequenced with evidence that approximately 30 % of cases harbour mutations of the histone H3.3 gene. Although studies to determinate their role in risk stratification are on-going, it remains to be determined whether H3.3 mutations could be found in other tumors such as pediatric primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) and whether the presence of H3.3 mutations in glioblastomas could be used as diagnostic tool in their differential diagnosis with CNS-PNETs. We performed a large mutational pyrosequencing-based screening on 123 pediatric glioblastomas and 33 CNS-PNET. The analysis revealed that 39/123 (31.7 %) glioblastomas carry H3.3 mutations. The K27M (AAG → ATG, lysine → methionine) mutation was found in 33 glioblastomas (26 %); the G34R (GGG → AGG, glycine → arginine) was observed in 6 glioblastomas (5.5 %). However, we also identified 4 of 33 cases (11 %) of CNS-PNETs harbouring a H3.3 G34R mutation. Multiplex ligation-dependent probe amplification analysis revealed PDGFR-alpha amplification and EGFR gain in two cases and N-Myc amplification in one case of H3.3 G34R mutated CNS-PNET. None of H3.3 mutated tumors presented a CDKN2A loss. In conclusion, because pediatric patients with glioblastoma and CNS-PNET are treated according to different therapeutic protocols, these findings may raise further concerns about the reliability of the histological diagnosis in the case of an undifferentiated brain tumor harbouring G34R H3.3 mutation. In this view, additional studies are needed to determine whether H3.3 G34 mutated CNS-PNET/glioblastomas may represent a defined tumor subtype.

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All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany

    Marco Gessi, Gerrit H. Gielen, Jennifer Hammes, Evelyn Dörner, Anja zur Mühlen, Andreas Waha & Torsten Pietsch

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  1. Marco Gessi
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  2. Gerrit H. Gielen
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  3. Jennifer Hammes
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  4. Evelyn Dörner
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  5. Anja zur Mühlen
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  6. Andreas Waha
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  7. Torsten Pietsch
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Corresponding author

Correspondence to Marco Gessi.

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Marco Gessi and Gerrit H. Gielen contributed equally to this work.

Andreas Waha and Torsten Pietsch share senior authorship.

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Gessi, M., Gielen, G.H., Hammes, J. et al. H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: possible diagnostic and therapeutic implications?. J Neurooncol 112, 67–72 (2013). https://doi.org/10.1007/s11060-012-1040-z

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  • DOI: https://doi.org/10.1007/s11060-012-1040-z

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