Risk stratification of H3 K27M–mutant diffuse midline gliomas based on anatomical locations: an integrated systematic review of individual participant data

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  • 1 Department of Neurosurgery, The University of Oklahoma Health Sciences Center, Oklahoma University, Oklahoma City, Oklahoma;
  • | 2 Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam; and
  • | 3 Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma University, Oklahoma City, Oklahoma
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OBJECTIVE

The prognostic significance and genetic characteristics of H3 K27M–mutant diffuse midline gliomas (DMGs) in different anatomical locations requires further clarification. In this study, the authors integrated published data to investigate the differences between brainstem, thalamic, and spinal cord tumors.

METHODS

PubMed and Web of Science databases were used to search for eligible articles. Studies were included if they provided individual patient data of H3 K27M–mutant DMGs with available tumor locations. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed to investigate the survival of each subgroup.

RESULTS

Eight hundred four tumors were identified, including 467, 228, and 109 in the brainstem, thalamus, and spine, respectively. Brainstem tumors were primarily observed in young children, while patients with thalamic and spinal cord tumors afflicted older patients. The Ki-67 labeling index was highest in brainstem tumors. Compared to patients with brainstem tumors, those with thalamic (HR 0.573, 95% CI 0.463–0.709; p < 0.001) and spinal cord lesions (HR 0.460, 95% CI 0.341–0.621; p < 0.001) had a significantly better survival. When patients were stratified by age groups, superior overall survival (OS) of thalamic tumors was observed in comparison to brainstem tumors in young children and adolescents, whereas adult tumors had uniform OS regardless of anatomical sites. Genetically, mutations in HIST1H3B/C (H3.1) and ACVR1 genes were mostly detected in brainstem tumors, whereas spinal cord tumors were characterized by a higher incidence of mutations in the TERT promoter.

CONCLUSIONS

This study demonstrated that H3 K27M–mutant DMGs have distinct clinical characteristics, prognoses, and molecular profiles in different anatomical locations.

ABBREVIATIONS

CI = confidence interval; DMG = diffuse midline glioma; HR = hazard ratio; IPD = individual patient data; NOS = Newcastle-Ottawa Scale; OS = overall survival; PFS = progression-free survival.

Supplementary Materials

    • Figures S1 and S2 (PDF 742 KB)
Illustration from Cinalli et al. (pp 119–127). Printed with permission from © CC Medical Arts.

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  • 1

    Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012;124(3):439447.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet. 2014;46(5):444450.

  • 3

    Buczkowicz P, Hoeman C, Rakopoulos P, et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet. 2014;46(5):451456.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Korshunov A, Ryzhova M, Hovestadt V, et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol. 2015;129(5):669678.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803820.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):12311251.

  • 7

    Castel D, Philippe C, Calmon R, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 2015;130(6):815827.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Wang YZ, Zhang YW, Liu WH, et al. Spinal cord diffuse midline gliomas With H3 K27m-mutant: clinicopathological features and prognosis. Neurosurgery. 2021;89(2):300307.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Vuong HG, Le HT, Ngo TNM, et al. H3K27M-mutant diffuse midline gliomas should be further molecularly stratified: an integrated analysis of 669 patients. J Neurooncol. 2021;155(3):225234.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Feng J, Hao S, Pan C, et al. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol. 2015;46(11):16261632.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Wang L, Li Z, Zhang M, et al. H3 K27M-mutant diffuse midline gliomas in different anatomical locations. Hum Pathol. 2018;78:8996.

  • 12

    Karremann M, Gielen GH, Hoffmann M, et al. Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro Oncol. 2018;20(1):123131.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603605.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Aihara K, Mukasa A, Gotoh K, et al. H3F3A K27M mutations in thalamic gliomas from young adult patients. Neuro Oncol. 2014;16(1):140146.

  • 15

    Akinduro OO, Garcia DP, Higgins DMO, et al. A multicenter analysis of the prognostic value of histone H3 K27M mutation in adult high-grade spinal glioma. J Neurosurg Spine. 2021;35(6):834843.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Alvi MA, Ida CM, Paolini MA, et al. Spinal cord high-grade infiltrating gliomas in adults: clinico-pathological and molecular evaluation. Mod Pathol. 2019;32(9):12361243.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Bruzek AK, Ravi K, Muruganand A, et al. Electronic DNA analysis of CSF cell-free tumor DNA to quantify multi-gene molecular response in pediatric high-grade glioma. Clin Cancer Res. 2020;26(23):62666276.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Chiba K, Aihara Y, Masui K, Abe K, Komori T, Kawamata T. Pulvinar locus is highly relevant to patients’ outcomes in surgically resected thalamic gliomas in children. World Neurosurg. 2020;134:e530e539.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Crotty EE, Leary SES, Geyer JR, et al. Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children’s Hospital experience. J Neurooncol. 2020;148(3):607617.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Daoud EV, Rajaram V, Cai C, et al. Adult brainstem gliomas with H3K27M mutation: radiology, pathology, and prognosis. J Neuropathol Exp Neurol. 2018;77(4):302311.

  • 21

    Dono A, Takayasu T, Ballester LY, Esquenazi Y. Adult diffuse midline gliomas: clinical, radiological, and genetic characteristics. J Clin Neurosci. 2020;82(Pt A):18.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Dorfer C, Czech T, Gojo J, et al. Infiltrative gliomas of the thalamus in children: the role of surgery in the era of H3 K27M mutant midline gliomas. Acta Neurochir (Wien). 2021;163(7):20252035.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Ebrahimi A, Skardelly M, Schuhmann MU, et al. High frequency of H3 K27M mutations in adult midline gliomas. J Cancer Res Clin Oncol. 2019;145(4):839850.

  • 24

    Eschbacher KL, Ida CM, Johnson DR, et al. Diffuse gliomas of the brainstem and cerebellum in adults show molecular heterogeneity. Am J Surg Pathol. 2021;45(8):10821090.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet. 2014;46(5):462466.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Garibotto F, Madia F, Milanaccio C, et al. 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. 2020;10:795.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Gessi M, Gielen GH, Dreschmann V, Waha A, Pietsch T. High frequency of H3F3A (K27M) mutations characterizes pediatric and adult high-grade gliomas of the spinal cord. Acta Neuropathol. 2015;130(3):435437.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Giagnacovo M, Antonelli M, Biassoni V, et al. Retrospective analysis on the consistency of MRI features with histological and molecular markers in diffuse intrinsic pontine glioma (DIPG). Childs Nerv Syst. 2020;36(4):697704.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Gojo J, Pavelka Z, Zapletalova D, et al. Personalized treatment of H3K27M-mutant pediatric diffuse gliomas provides improved therapeutic opportunities. Front Oncol. 2020;9:1436.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Grasso CS, Tang Y, Truffaux N, et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med. 2015;21(6):555559.

  • 31

    Hoffman LM, DeWire M, Ryall S, et al. Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun. 2016;4:1.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Karlowee V, Amatya VJ, Takayasu T, et al. Immunostaining of increased expression of enhancer of zeste homolog 2 (EZH2) in diffuse midline glioma H3K27M-mutant patients with poor survival. Pathobiology. 2019;86(2-3):152161.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Kleinschmidt-DeMasters BK, Mulcahy Levy JM. H3 K27M-mutant gliomas in adults vs. children share similar histological features and adverse prognosis. Clin Neuropathol. 2018;37(2):5363.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Liu Y, Zhang Y, Hua W, Li Z, Wu B, Liu W. Clinical and molecular characteristics of thalamic gliomas: retrospective report of 26 cases. World Neurosurg. 2019;126:e1169e1182.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Mackay A, Burford A, Carvalho D, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell. 2017;32(4):520537.e5.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Mackay A, Burford A, Molinari V, et al. Molecular, pathological, radiological, and immune profiling of non-brainstem pediatric high-grade glioma from the HERBY Phase II randomized trial. Cancer Cell. 2018;33(5):829842.e5.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Meyronet D, Esteban-Mader M, Bonnet C, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol. 2017;19(8):11271134.

  • 38

    Mueller S, Jain P, Liang WS, et al. 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. 2019;145(7):18891901.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Pan C, Diplas BH, Chen X, et al. Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA. Acta Neuropathol. 2019;137(2):297306.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Panditharatna E, Kilburn LB, Aboian MS, et al. Clinically relevant and minimally invasive tumor surveillance of pediatric diffuse midline gliomas using patient-derived liquid biopsy. Clin Cancer Res. 2018;24(23):58505859.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Picca A, Berzero G, Bielle F, et al. FGFR1 actionable mutations, molecular specificities, and outcome of adult midline gliomas. Neurology. 2018;90(23):e2086e2094.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Ryall S, Krishnatry R, Arnoldo A, et al. Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma. Acta Neuropathol Commun. 2016;4(1):93.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012;482(7384):226231.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Sievers P, Sill M, Schrimpf D, et al. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro Oncol. 2021;23(1):3443.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Sturm D, Witt H, Hovestadt V, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22(4):425437.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Taylor KR, Mackay A, Truffaux N, et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet. 2014;46(5):457461.

  • 47

    Wang Y, Feng LL, Ji PG, et al. Clinical features and molecular markers on diffuse midline gliomas with H3K27M mutations: a 43 cases retrospective cohort study. Front Oncol. 2021;10:602553.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Yi S, Choi S, Shin DA, et al. 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. 2019;84(5):10721081.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Zhou C, Zhao H, Yang F, et al. Clinical and genetic features of brainstem glioma in adults: a report of 50 cases in a single center. J Clin Neurol. 2021;17(2):220228.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50

    Lu VM, Alvi MA, McDonald KL, Daniels DJ. Impact of the H3K27M mutation on survival in pediatric high-grade glioma: a systematic review and meta-analysis. J Neurosurg Pediatr. 2018;23(3):308316.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Vuong HG, Tran TTK, Ngo HTT, et al. 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. 2019;26(3):379387.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Vuong HG, Ngo HTT, Le HT, et al. Prognostic implication of patient age in H3K27M-mutant midline gliomas. Front Oncol. 2022;12:858148.

  • 53

    Grimaldi S, Harlay V, Appay R, et al. Adult H3K27M mutated thalamic glioma patients display a better prognosis than unmutated patients. J Neurooncol. 2022;156(3):615623.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Biczok A, Strübing FL, Eder JM, et al. Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas. Acta Neuropathol Commun. 2021;9(1):119.

  • 55

    Vuong HG, Altibi AMA, Duong UNP, et al. TERT promoter mutation and its interaction with IDH mutations in glioma: Combined TERT promoter and IDH mutations stratifies lower-grade glioma into distinct survival subgroups—A meta-analysis of aggregate data. Crit Rev Oncol Hematol. 2017;120:19.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Vuong HG, Nguyen TQ, Ngo TNM, Nguyen HC, Fung KM, Dunn IF. The interaction between TERT promoter mutation and MGMT promoter methylation on overall survival of glioma patients: a meta-analysis. BMC Cancer. 2020;20(1):897.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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