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Clinical and Molecular Features of Patients with Gliomas Harboring IDH1 Non-canonical Mutations: A Systematic Review and Meta-Analysis

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Abstract

Introduction

The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH-mutated gliomas. Non-canonical IDH1 mutations or IDH2 mutations are unusual and their clinical and biological role is still unclear.

Methods

We performed a systematic review and meta-analysis to assess the clinical role of IDH non-canonical mutations.

Results

Overall, we selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 glioma including 3091 patients with a molecularly proven IDH1 or IDH2 mutation. Patients with non-canonical IDH1 mutations were younger and presented a higher DNA methylation level as compared to those with canonical IDH1 R132H alteration. The overall incidence of non-canonical IDH1 mutations was 7.9% (95% CI 5.4–10.7%) in patients with IDH-mutated gliomas. There was no statistical difference in terms of incidence between patients with grade 2 or grade 3 glioma. Patients with non-canonical IDH mutations had a lower rate of 1p19q codeletion (risk difference 31%, 95% CI 23–38%) and presented a significantly prolonged survival (pooled HR 0.47, 95% CI 0.28–0.81) as compared to those with IDH1 R132H mutation.

Conclusion

Non-canonical IDH1 mutations occur in 7.9% of IDH-mutated gliomas and identify a specific subgroup of patients with an improved survival despite a lower rate of 1p19q codeletion. Data about the type of IDH mutation should be collected in clinical practice and within interventional trials as this could be a critical variable for improved stratification and selection of patients.

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References

  1. 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):803–20. https://doi.org/10.1007/s00401-016-1545-1.

    Article  PubMed  Google Scholar 

  2. Ostrom QT, Cioffi G, Gittleman H, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol. 2019;21(Suppl 5):v1–100. https://doi.org/10.1093/neuonc/noz150.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170–86. https://doi.org/10.1038/s41571-020-00447-z.

    Article  PubMed  Google Scholar 

  4. Brat DJ, Verhaak RG, Aldape KD, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372(26):2481–98. https://doi.org/10.1056/NEJMoa1402121.

    Article  CAS  PubMed  Google Scholar 

  5. Mair MJ, Geurts M, van den Bent MJ, Berghoff AS. A basic review on systemic treatment options in WHO grade II-III gliomas. Cancer Treat Rev. 2021;92: 102124. https://doi.org/10.1016/j.ctrv.2020.102124.

    Article  PubMed  Google Scholar 

  6. Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27(25):4150–4. https://doi.org/10.1200/jco.2009.21.9832.

    Article  CAS  PubMed  Google Scholar 

  7. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73. https://doi.org/10.1056/NEJMoa0808710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang HY, Tang K, Liang TY, et al. The comparison of clinical and biological characteristics between IDH1 and IDH2 mutations in gliomas. J Exp Clin Cancer Res. 2016;35:86. https://doi.org/10.1186/s13046-016-0362-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tesileanu CMS, Vallentgoed WR, Sanson M, et al. Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations. Acta Neuropathol. 2021;141(6):945–57. https://doi.org/10.1007/s00401-021-02291-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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):603–5. https://doi.org/10.1007/s10654-010-9491-z.

    Article  PubMed  Google Scholar 

  11. Poetsch L, Bronnimann C, Loiseau H, et al. Characteristics of IDH-mutant gliomas with non-canonical IDH mutation. J Neurooncol. 2021;151(2):279–86. https://doi.org/10.1007/s11060-020-03662-x.

    Article  CAS  PubMed  Google Scholar 

  12. Metellus P, Coulibaly B, Colin C, et al. Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol. 2010;120(6):719–29. https://doi.org/10.1007/s00401-010-0777-8.

    Article  PubMed  Google Scholar 

  13. Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469–74. https://doi.org/10.1007/s00401-009-0561-9.

    Article  PubMed  Google Scholar 

  14. Gravendeel LA, Kloosterhof NK, Bralten LB, et al. Segregation of non-pR132H mutations in IDH1 in distinct molecular subtypes of glioma. Hum Mutat. 2010;31(3):E1186–99. https://doi.org/10.1002/humu.21201.

    Article  CAS  PubMed  Google Scholar 

  15. Franceschi E, De Biase D, Di Nunno V, et al. IDH1 non-canonical mutations and survival in patients with glioma. Diagnostics (Basel). 2021. https://doi.org/10.3390/diagnostics11020342.

    Article  PubMed Central  Google Scholar 

  16. Chen N, Yu T, Gong J, et al. IDH1/2 gene hotspot mutations in central nervous system tumours: analysis of 922 Chinese patients. Pathology. 2016;48(7):675–83. https://doi.org/10.1016/j.pathol.2016.07.010.

    Article  CAS  PubMed  Google Scholar 

  17. Camelo-Piragua S, Jansen M, Ganguly A, et al. A sensitive and specific diagnostic panel to distinguish diffuse astrocytoma from astrocytosis: chromosome 7 gain with mutant isocitrate dehydrogenase 1 and p53. J Neuropathol Exp Neurol. 2011;70(2):110–5. https://doi.org/10.1097/NEN.0b013e31820565f9.

    Article  CAS  PubMed  Google Scholar 

  18. Bell EH, Zhang P, Shaw EG, et al. Comprehensive genomic analysis in NRG oncology/RTOG 9802: a phase III trial of radiation versus radiation plus procarbazine, lomustine (CCNU), and vincristine in high-risk low-grade glioma. J Clin Oncol. 2020;38(29):3407–17. https://doi.org/10.1200/jco.19.02983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116(6):597–602. https://doi.org/10.1007/s00401-008-0455-2.

    Article  CAS  PubMed  Google Scholar 

  20. Ceccarelli M, Barthel FP, Malta TM, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell. 2016;164(3):550–63. https://doi.org/10.1016/j.cell.2015.12.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. van den Bent MJ, Baumert B, Erridge SC, et al. Interim results from the CATNON trial (EORTC study 26053–22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017;390(10103):1645–53. https://doi.org/10.1016/s0140-6736(17)31442-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. van den Bent MJ, Klein M, Smits M, et al. Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC): a randomised controlled phase 2 EORTC trial. Lancet Oncol. 2018;19(9):1170–9. https://doi.org/10.1016/s1470-2045(18)30362-0.

    Article  CAS  PubMed  Google Scholar 

  23. 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):1231–51. https://doi.org/10.1093/neuonc/noab106.

    Article  CAS  PubMed  Google Scholar 

  24. Tesileanu CMS, van den Bent MJ, Sanson M, et al. Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma. Neuro Oncol. 2021;23(9):1547–59. https://doi.org/10.1093/neuonc/noab088.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Han S, Liu Y, Cai SJ, et al. IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. Br J Cancer. 2020;122(11):1580–9. https://doi.org/10.1038/s41416-020-0814-x.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lo CK, Mertz D, Loeb M. Newcastle-Ottawa Scale: comparing reviewers’ to authors’ assessments. BMC Med Res Methodol. 2014;14:45. https://doi.org/10.1186/1471-2288-14-45.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Visani M, de Biase D, Marucci G, et al. Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I-III. Mol Oncol. 2014;8(2):417–30. https://doi.org/10.1016/j.molonc.2013.12.010.

    Article  CAS  PubMed  Google Scholar 

  28. Ferreyra Vega S, Olsson Bontell T, Corell A, Smits A, Jakola AS, Carén H. DNA methylation profiling for molecular classification of adult diffuse lower-grade gliomas. Clin Epigenet. 2021;13(1):102. https://doi.org/10.1186/s13148-021-01085-7.

    Article  CAS  Google Scholar 

  29. Pirozzi CJ, Yan H. The implications of IDH mutations for cancer development and therapy. Nat Rev Clin Oncol. 2021. https://doi.org/10.1038/s41571-021-00521-0.

    Article  PubMed  Google Scholar 

  30. Gatto L, Franceschi E, Tosoni A, et al. IDH inhibitors and beyond: the cornerstone of targeted glioma treatment. Mol Diagn Ther. 2021. https://doi.org/10.1007/s40291-021-00537-3.

    Article  PubMed  Google Scholar 

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Acknowledgements

Funding

No funding or sponsorship was received for this study or publication of this article.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contribution

EF, VDN, AAB, conceptualization. EF, VDN, AT, LG, IM, SB, DA, writing, software and data curation. VDN, EF, statistical analyses. AAB and RL, supervision, visualization and investigation. All authors helped in review and editing.

Disclosures

All authors (Vincenzo Di Nunno, Enrico Franceschi, Alicia Tosoni, Lidia Gatto, Ilaria Maggio, Daniele Angelini, Stefania Bartolini, Raffaele Lodi, Alba Ariela Brandes) all have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Authors and Affiliations

  1. Department of Oncology, AUSL Bologna, Bologna, Italy

    Vincenzo Di Nunno, Lidia Gatto & Ilaria Maggio

  2. Nervous System Medical Oncology Department, IRCCS Istituto Scienze Neurologiche, Via Altura 3, Bologna, Italy

    Enrico Franceschi, Alicia Tosoni, Daniele Angelini, Stefania Bartolini & Alba Ariela Brandes

  3. IRCCS Istituto delle Scienze Neuroradiologiche di Bologna, Bologna, Italy

    Raffaele Lodi

  4. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

    Raffaele Lodi

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  1. Vincenzo Di Nunno
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Corresponding author

Correspondence to Enrico Franceschi.

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Di Nunno, V., Franceschi, E., Tosoni, A. et al. Clinical and Molecular Features of Patients with Gliomas Harboring IDH1 Non-canonical Mutations: A Systematic Review and Meta-Analysis. Adv Ther 39, 165–177 (2022). https://doi.org/10.1007/s12325-021-01977-3

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  • DOI: https://doi.org/10.1007/s12325-021-01977-3

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