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Evaluating H3F3A K27M and G34R/V somatic mutations in a cohort of pediatric brain tumors of different and rare histologies

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Abstract

Purpose

Somatic mutations on H3 histone are currently considered a genetic hallmark for midline pediatric high-grade gliomas (HGGs). Yet, different tumor histologies have been occasionally described to carry these mutations. Since histone modifications can lead to major epigenetic changes with direct impact on prognosis and treatment, we thought to investigate the occurrence of H3F3A K27M and G34R/V mutations in a cohort of pediatric tumors which included HGGs, low-grade gliomas, ependymomas, medulloblastomas, and a series of rare brain tumor lesions of different histologies.

Methods

A total of 82 fresh-frozen pediatric brain tumor samples were evaluated. PCR or RT-PCR followed by Sanger sequencing for the exon 2 of H3F3A (containing both K27 and G34 hotspots) were obtained and aligned to human genome. Loss of trimethylation mark (H3K27me3) in H3F3A/K27M-mutant samples was confirmed by immunohistochemistry.

Results

We found H3F3A/K27M mutation in 2 out of 9 cases of HGGs; no H3F3A/K27M mutations were detected in low-grade gliomas (27), ependymomas (n = 10), medulloblastomas (n = 21), or a series of rare pediatric brain tumors which included meningiomas, dysembryoplastic neuroepithelial tumors (DNETs), central nervous system (CNS) germ-cell tumors, choroid plexus tumors, cortical hamartoma, subcortical tubers, and schwannomas (n = 15). H3F3A/G34R/V mutation was not observed in any of the samples.

Conclusions

Our investigation reinforces the low frequency of H3F3A somatic mutations outside the HGG setting. Interestingly, an atypical focal brainstem glioma carrying H3F3A K27M mutation that showed protracted clinical course with late-onset tumor progression was identified.

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Data availability

All data generated from this study are presented in this article.

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Acknowledgments

We thank Dr. Luciano Neder for pathological assistance and expertise on cases.

Funding

FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo – grant no. 2018/20275-8)/Brazil, as part of Scientific Initiation Program (granted by Medical Student Vinicius Fernandes Oliveira)

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Author notes

  1. Vinicius Fernandes Oliveira and Graziella Ribeiro de Sousa contributed equally to this work.

Authors and Affiliations

  1. Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Vinicius Fernandes Oliveira

  2. Department of Genetics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Graziella Ribeiro De Sousa

  3. Department of Oncology and Image, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Antonio Carlos dos Santos

  4. Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Fabiano Pinto Saggioro

  5. Division of Pediatric Neurosurgery, Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Helio Rubens Machado

  6. Division of Neurosurgery, Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Ricardo Santos de Oliveira

  7. Department of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, Bloco G, 1 Andar, Ribeirão Preto, SP, 14049-900, Brazil

    Luiz Gonzaga Tone & Elvis Terci Valera

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  1. Vinicius Fernandes Oliveira
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Contributions

E.T.V., V.F.O., and G.R.S. planned the study, conducted data analysis, and drafted the manuscript; F.P.S. performed data analysis and immunohistochemistry; A.C.S. performed image analysis and intellectual content; H.R.M., R.S.O., and L.G.T. proceeded sample collection and revised text for important intellectual content. V.F.O and G.R.S. wrote and organized the data, created the figures/tables, and edited and finalized the manuscript. All authors critically read and approved the final manuscript.

Corresponding author

Correspondence to Elvis Terci Valera.

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The authors declare that they have no competing interests.

Ethics approval

Tumor collection (brain tumor repository) was performed under the approval of the Institutional Review Board (IRB) (#6591/2007). This study was also Institutional Review Board (IRB) approved (CAAE# 14154819.6.0000.5440).

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Supplemental Figure 1.

IHC staining for H3K27me3 on 14 cases of pediatric midline gliomas H3F3A K27 wild-type, showing a retained pattern of this histone trimethylation marker. (JPG 10297 kb).

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Oliveira, V.F., De Sousa, G.R., dos Santos, A.C. et al. Evaluating H3F3A K27M and G34R/V somatic mutations in a cohort of pediatric brain tumors of different and rare histologies. Childs Nerv Syst 37, 375–382 (2021). https://doi.org/10.1007/s00381-020-04852-8

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