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The prognostic significance of HIST1H3B/C and H3F3A K27M mutations in diffuse midline gliomas is influenced by patient age

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Abstract

Introduction

Diffuse midline gliomas (DMGs) are infiltrative midline gliomas harboring H3K27M mutations and are generally associated with poor outcomes. H3K27M mutations include mutations in HIST1H3B/C (H3.1), HIST2H3B/D (H3.2), or H3F3A (H3.3) genes. It is still unclear whether these mutations each portend a universally poor prognosis, or if there are any factors which modulate outcome. The main objective of this study was to study overall survival (OS) of H3.1 versus H3.3 K27M-mutant DMGs in pediatric and adult patients.

Methods

PubMed and Web of Science were searched, and we included studies if they have individual patient data of DMGs with available H3K27M genotype. Kaplan–Meier analysis and Cox regression models were used to analyze the survival of H3.1 and H3.3 mutations in each subgroup.

Results

We included 26 studies with 102 and 529 H3.1 and H3.3-mutant DMGs, respectively. The H3.1 mutation was more commonly seen in younger age. In pediatric population, H3.3 mutation conferred a shorter survival (median OS of 10.1 vs 14.2 months; p < 0.001) in comparison to H3.1-positive patients, which was further confirmed in the multivariate Cox analysis. Conversely, H3.3 was associated with a prolonged survival in adult patients as compared with H3.1 mutation (median OS of 14.4 vs 1.7 months; p = 0.019).

Conclusion

We demonstrated that the prognosis of H3.1 and H3.3 K27M mutation in DMG patients is modulated by patient age. Routine H3K27M mutation genotyping in newly diagnosed DMGs may further stratify patients with these difficult tumors.

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Data availability

Further data inquiries can be directed to the corresponding author.

References

  1. Louis DN et al (2018) cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol 135(4):639–642

    Article  PubMed  Google Scholar 

  2. Hake SB, Allis CD (2006) Histone H3 variants and their potential role in indexing mammalian genomes: the “H3 barcode hypothesis.” Proc Natl Acad Sci 103(17):6428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schulte JD et al (2020) Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults. Neurooncol Adv 2(1):vdaa142

    PubMed  PubMed Central  Google Scholar 

  4. Schreck KC et al (2019) Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas. J Neurooncol 143(1):87–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Broniscer A, Gajjar A (2004) Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist 9(2):197–206

    Article  PubMed  Google Scholar 

  6. Picca A et al (2018) FGFR1 actionable mutations, molecular specificities, and outcome of adult midline gliomas. Neurology 90(23):e2086–e2094

    Article  CAS  PubMed  Google Scholar 

  7. Lynes J et al (2020) Variations in attitudes towards stereotactic biopsy of adult diffuse midline glioma patients: a survey of members of the AANS/CNS Tumor Section. J Neurooncol 149(1):161–170

    Article  PubMed  PubMed Central  Google Scholar 

  8. Louis DN et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820

    Article  PubMed  Google Scholar 

  9. Louis DN et al (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23(8):1231–1251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kleinschmidt-DeMasters BK, Mulcahy Levy JM (2018) H3 K27M-mutant gliomas in adults vs. children share similar histological features and adverse prognosis. Clin Neuropathol 37(2):53–63

    Article  PubMed  PubMed Central  Google Scholar 

  11. Castel D et al (2015) Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130(6):815–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sturm D et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22(4):425–437

    Article  CAS  PubMed  Google Scholar 

  13. Ebrahimi A et al (2019) High frequency of H3 K27M mutations in adult midline gliomas. J Cancer Res Clin Oncol 145(4):839–850

    Article  CAS  PubMed  Google Scholar 

  14. Moher D et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097

    PubMed  PubMed Central  Google Scholar 

  15. Aihara K et al (2014) H3F3A K27M mutations in thalamic gliomas from young adult patients. Neuro Oncol 16(1):140–146

    Article  CAS  PubMed  Google Scholar 

  16. Bruzek AK et al (2020) Electronic DNA analysis of CSF cell-free tumor DNA to quantify multi-gene molecular response in pediatric high-grade glioma. Clin Cancer Res 26(23):6266–6276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Buczkowicz P et al (2014) Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46(5):451–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chiba K et al (2020) Pulvinar locus is highly relevant to patients’ outcomes in surgically resected thalamic gliomas in children. World Neurosurg 134:e530–e539

    Article  PubMed  Google Scholar 

  19. Crotty EE et al (2020) Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children’s Hospital experience. J Neurooncol 148(3):607–617

    Article  CAS  PubMed  Google Scholar 

  20. Dono A et al (2020) Adult diffuse midline gliomas: clinical, radiological, and genetic characteristics. J Clin Neurosci 82(Pt A):1–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Eschbacher KL et al (2021) Diffuse gliomas of the brainstem and cerebellum in adults show molecular heterogeneity. Am J Surg Pathol 45(8):1082–1090

    Article  PubMed  Google Scholar 

  22. Fukami S et al (2018) Pathologic findings and clinical course of midline paraventricular gliomas diagnosed using a neuroendoscope. World Neurosurg 114:e366–e377

    Article  PubMed  Google Scholar 

  23. Garibotto F et al (2020) Pediatric diffuse midline gliomas H3 K27M-mutant and non-histone mutant midline high-grade gliomas in neurofibromatosis type 1 in comparison with non-syndromic children: a single-center pilot study. Front Oncol 10:795

    Article  PubMed  PubMed Central  Google Scholar 

  24. Giagnacovo M et al (2020) Retrospective analysis on the consistency of MRI features with histological and molecular markers in diffuse intrinsic pontine glioma (DIPG). Childs Nerv Syst 36(4):697–704

    Article  PubMed  Google Scholar 

  25. Gojo J et al (2019) Personalized treatment of H3K27M-mutant pediatric diffuse gliomas provides improved therapeutic opportunities. Front Oncol 9:1436

    Article  PubMed  Google Scholar 

  26. Hoffman LM et al (2016) Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 4:1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Mackay A et al (2018) Molecular, pathological, radiological, and immune profiling of non-brainstem pediatric high-grade glioma from the HERBY phase II randomized trial. Cancer Cell 33(5):829-842.e5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meyronet D et al (2017) Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol 19(8):1127–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mueller S et al (2019) A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: a report from the Pacific Pediatric Neuro-Oncology Consortium. Int J Cancer 145(7):1889–1901

    CAS  PubMed  Google Scholar 

  30. Nomura M et al (2017) Distinct molecular profile of diffuse cerebellar gliomas. Acta Neuropathol 134(6):941–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pan C et al (2019) Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA. Acta Neuropathol 137(2):297–306

    Article  CAS  PubMed  Google Scholar 

  32. Reinhardt A et al (2019) Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities. Acta Neuropathol Commun 7(1):1–12

    Article  CAS  Google Scholar 

  33. Reuss DE et al (2015) Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol 130(3):407–417

    Article  CAS  PubMed  Google Scholar 

  34. Sievers P et al (2021) A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro Oncol 23(1):34–43

    Article  CAS  PubMed  Google Scholar 

  35. Taylor KR et al (2014) Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46(5):457–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yi S et al (2019) Impact of H3.3 K27M mutation on prognosis and survival of grade IV spinal cord glioma on the basis of new 2016 World Health Organization classification of the central nervous system. Neurosurgery 84(5):1072–1081

    Article  PubMed  Google Scholar 

  37. Vuong HG et al (2019) Prognostic significance of genetic biomarkers in isocitrate dehydrogenase-wild-type lower-grade glioma: the need to further stratify this tumor entity - a meta-analysis. Eur J Neurol 26(3):379–387

    Article  CAS  PubMed  Google Scholar 

  38. Tang MC et al (2015) Contribution of the two genes encoding histone variant H3.3 to viability and fertility in mice. PLoS Genet 11(2):e1004964

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Vuong HG et al (2022) Risk stratification of H3 K27M–mutant diffuse midline gliomas based on anatomical locations: an integrated systematic review of individual participant data. J Neurosurg Pediatr. https://doi.org/10.3171/2022.3.PEDS2250

    Article  PubMed  Google Scholar 

  40. Khuong-Quang DA et al (2012) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124(3):439–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vuong HG et al (2022) Prognostic implication of patient age in H3K27M-mutant midline gliomas. Front Oncol 12:1–8

    Article  Google Scholar 

  42. Sarthy JF et al (2020) Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones. Elife 9:e61090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tagami H et al (2004) Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116(1):51–61

    Article  CAS  PubMed  Google Scholar 

  44. Castel D et al (2018) Transcriptomic and epigenetic profiling of “diffuse midline gliomas, H3 K27M-mutant” discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location. Acta Neuropathol Commun 6(1):117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hoffman LM et al (2018) Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG Registries. J Clin Oncol 36(19):1963–1972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vuong HG et al (2021) H3K27M-mutant diffuse midline gliomas should be further molecularly stratified: an integrated analysis of 669 patients. J Neurooncol 155(3):225–234

    Article  CAS  PubMed  Google Scholar 

  47. Fortin J et al (2020) Mutant ACVR1 arrests glial cell differentiation to drive tumorigenesis in pediatric gliomas. Cancer Cell 37(3):308-323.e12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wu G et al (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46(5):444–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Weller M et al (2021) EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol 18(3):170–186

    Article  PubMed  Google Scholar 

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Acknowledgements

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Funding

This study receives no funding support.

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Authors and Affiliations

  1. Department of Neurosurgery, Oklahoma University Health Sciences Center, Oklahoma City, OK, 73104, USA

    Huy Gia Vuong & Ian F. Dunn

  2. Faculty of Medicine, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, 700-000, Vietnam

    Tam N. M. Ngo

  3. Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, 700-000, Vietnam

    Hieu Trong Le

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  1. Huy Gia Vuong
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  4. Ian F. Dunn
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Contributions

HGV: conceptualization, data curation, formal analysis, investigation, methodology, project administration, software, validation, writing original, review, and editing. TNNM: data curation, formal analysis, investigation, methodology, writing original, review, and editing. HTL: data curation, formal analysis, investigation, methodology, review, and editing. IFD: data curation, formal analysis, investigation, methodology, project administration, validation, review, editing, and supervision. All authors have read and approved the manuscript.

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Correspondence to Ian F. Dunn.

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Vuong, H.G., Ngo, T.N.M., Le, H.T. et al. The prognostic significance of HIST1H3B/C and H3F3A K27M mutations in diffuse midline gliomas is influenced by patient age. J Neurooncol 158, 405–412 (2022). https://doi.org/10.1007/s11060-022-04027-2

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  • DOI: https://doi.org/10.1007/s11060-022-04027-2

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