Skip to main content
SpringerLink
Log in

IDH1 mutation in human glioma induces chemical alterations that are amenable to optical Raman spectroscopy

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Introduction

Mutations in the isocytrate dehydrogenase 1 (IDH1) gene are early genetic events in glioma pathogenesis and cause profound metabolic changes. Because this genotype is found in virtually every tumor cell, therapies targeting mutant IDH1 protein are being developed. The intraoperative administration of those therapies would require fast technologies for the determination of IDH1 genotype. As of today, there is no such diagnostic test available. Recently, infrared spectroscopy was shown to bridge this gap. Here, we tested Raman spectroscopy for analysis of IDH1 genotype in glioma, which constitutes an alternative contact-free technique with the potential of being applicable in situ.

Methods

Human glioma samples (n = 36) were obtained during surgery and cryosections were prepared. IDH1 mutations were assessed using DNA sequencing and 100 Raman spectra were obtained for each sample.

Results

Analysis of Raman spectra revealed increased intensities in spectral bands related to DNA in IDH1 mutant glioma while bands assigned to molecular vibrations of lipids were significantly decreased. Moreover, intensities of Raman bands assigned to proteins differed in IDH1 mutant and IDH1 wild-type glioma, suggesting alterations in the protein profile. The selection of five bands (498, 826, 1003, 1174 and 1337 cm−1) allowed the classification of Raman spectra according to IDH1 genotype with a correct rate of 89%.

Conclusion

Raman spectroscopy constitutes a simple, rapid and safe procedure for determination of the IDH1 mutation that shows great promise for clinically relevant in situ diagnostics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol (Berl) 131:803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  Google Scholar 

  2. Balss J, Meyer J, Mueller W et al (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol (Berl) 116:597–602. https://doi.org/10.1007/s00401-008-0455-2

    Article  CAS  Google Scholar 

  3. Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. https://doi.org/10.1056/NEJMoa0808710

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Houillier C, Wang X, Kaloshi G et al (2010) IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75:1560–1566. https://doi.org/10.1212/WNL.0b013e3181f96282

    Article  PubMed  CAS  Google Scholar 

  5. SongTao Q, Lei Y, Si G et al (2012) IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci 103:269–273. https://doi.org/10.1111/j.1349-7006.2011.02134.x

    Article  PubMed  CAS  Google Scholar 

  6. Tran AN, Lai A, Li S et al (2014) Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry. Neuro-Oncology 16:414–420. https://doi.org/10.1093/neuonc/not198

    Article  PubMed  CAS  Google Scholar 

  7. Dang L, White DW, Gross S et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744. https://doi.org/10.1038/nature08617

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Johnson BE, Mazor T, Hong C et al (2014) Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189–193. https://doi.org/10.1126/science.1239947

    Article  PubMed  CAS  Google Scholar 

  9. Lass U, Nümann A, von Eckardstein K et al (2012) Clonal analysis in recurrent astrocytic, oligoastrocytic and oligodendroglial tumors implicates IDH1- mutation as common tumor initiating event. PLoS ONE 7:e41298. https://doi.org/10.1371/journal.pone.0041298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Chen J, Yang J, Cao P (2016) The evolving landscape in the development of isocitrate dehydrogenase mutant inhibitors. Mini-Rev Med Chem. https://doi.org/10.2174/1389557516666160609085520

    Article  PubMed Central  PubMed  Google Scholar 

  11. Rohle D, Popovici-Muller J, Palaskas N et al (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340:626–630. https://doi.org/10.1126/science.1236062

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Pusch S, Krausert S, Fischer V et al (2017) Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol (Berl) 133:629–644. https://doi.org/10.1007/s00401-017-1677-y

    Article  CAS  Google Scholar 

  13. Sulkowski PL, Corso CD, Robinson ND et al (2017) 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aal2463

    Article  PubMed  PubMed Central  Google Scholar 

  14. Schumacher T, Bunse L, Pusch S et al (2014) A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512:324–327. https://doi.org/10.1038/nature13387

    Article  PubMed  CAS  Google Scholar 

  15. Pellegatta S, Valletta L, Corbetta C et al (2015) Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma. Acta Neuropathol Commun 3:4. https://doi.org/10.1186/s40478-014-0180-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Andronesi OC, Kim GS, Gerstner E et al (2012) Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med 4:116ra4. https://doi.org/10.1126/scitranslmed.3002693

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Choi C, Ganji SK, DeBerardinis RJ et al (2012) 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18:624–629. https://doi.org/10.1038/nm.2682

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tietze A, Choi C, Mickey B et al (2018) Noninvasive assessment of isocitrate dehydrogenase mutation status in cerebral gliomas by magnetic resonance spectroscopy in a clinical setting. J Neurosurg 128:391–398. https://doi.org/10.3171/2016.10.JNS161793

    Article  PubMed  Google Scholar 

  19. Juratli TA, Peitzsch M, Geiger K et al (2013) Accumulation of 2-hydroxyglutarate is not a biomarker for malignant progression in IDH-mutated low-grade gliomas. Neuro-Oncology 15:682–690. https://doi.org/10.1093/neuonc/not006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ohka F, Yamamichi A, Kurimoto M et al (2017) A novel all-in-one intraoperative genotyping system for IDH1-mutant glioma. Brain Tumor Pathol 34:91–97. https://doi.org/10.1007/s10014-017-0281-0

    Article  PubMed  CAS  Google Scholar 

  21. Uckermann O, Juratli TA, Galli R et al (2017) Optical analysis of glioma: Fourier-transform infrared spectroscopy reveals the IDH1 mutation status. Clin Cancer Res Off J Am Assoc Cancer Res. https://doi.org/10.1158/1078-0432.CCR-17-1795

    Article  Google Scholar 

  22. Mackanos MA, Contag CH (2010) Fiber-optic probes enable cancer detection with FTIR spectroscopy. Trends Biotechnol 28:317–323. https://doi.org/10.1016/j.tibtech.2010.04.001

    Article  PubMed  CAS  Google Scholar 

  23. Ollesch J, Zaczek M, Heise HM et al (2017) Clinical application of infrared fibre-optic probes for the discrimination of colorectal cancer tissues and cancer grades. Vib Spectrosc 91:99–110. https://doi.org/10.1016/j.vibspec.2016.07.003

    Article  CAS  Google Scholar 

  24. Amharref N, Beljebbar A, Dukic S et al (2007) Discriminating healthy from tumor and necrosis tissue in rat brain tissue samples by Raman spectral imaging. Biochim Biophys Acta 1768:2605–2615. https://doi.org/10.1016/j.bbamem.2007.06.032

    Article  PubMed  CAS  Google Scholar 

  25. Kalkanis SN, Kast RE, Rosenblum ML et al (2014) Raman spectroscopy to distinguish grey matter, necrosis, and glioblastoma multiforme in frozen tissue sections. J Neurooncol 116:477–485. https://doi.org/10.1007/s11060-013-1326-9

    Article  PubMed  CAS  Google Scholar 

  26. Kast R, Auner G, Yurgelevic S et al (2015) Identification of regions of normal grey matter and white matter from pathologic glioblastoma and necrosis in frozen sections using Raman imaging. J Neurooncol 125:287–295. https://doi.org/10.1007/s11060-015-1929-4

    Article  PubMed  CAS  Google Scholar 

  27. Krafft C, Sobottka SB, Schackert G, Salzer R (2005) Near infrared Raman spectroscopic mapping of native brain tissue and intracranial tumors. Analyst 130:1070. https://doi.org/10.1039/b419232j

    Article  PubMed  CAS  Google Scholar 

  28. Uckermann O, Galli R, Tamosaityte S et al (2014) Label-free delineation of brain tumors by coherent anti-Stokes Raman scattering microscopy in an orthotopic mouse model and human glioblastoma. PLoS ONE 9:e107115. https://doi.org/10.1371/journal.pone.0107115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Broadbent B, Tseng J, Kast R et al (2016) Shining light on neurosurgery diagnostics using Raman spectroscopy. J Neurooncol 130:1–9. https://doi.org/10.1007/s11060-016-2223-9

    Article  PubMed  Google Scholar 

  30. Hollon T, Lewis S, Freudiger CW et al (2016) Improving the accuracy of brain tumor surgery via Raman-based technology. Neurosurg Focus 40:E9. https://doi.org/10.3171/2015.12.FOCUS15557

    Article  PubMed  PubMed Central  Google Scholar 

  31. Jermyn M, Mok K, Mercier J et al (2015) Intraoperative brain cancer detection with Raman spectroscopy in humans. Sci Transl Med 7:274ra19. https://doi.org/10.1126/scitranslmed.aaa2384

    Article  PubMed  CAS  Google Scholar 

  32. Beljebbar A, Dukic S, Amharref N, Manfait M (2010) Ex vivo and in vivo diagnosis of C6 glioblastoma development by Raman spectroscopy coupled to a microprobe. Anal Bioanal Chem 398:477–487. https://doi.org/10.1007/s00216-010-3910-6

    Article  PubMed  CAS  Google Scholar 

  33. Bergner N, Krafft C, Geiger KD et al (2012) Unsupervised unmixing of Raman microspectroscopic images for morphochemical analysis of non-dried brain tumor specimens. Anal Bioanal Chem 403:719–725. https://doi.org/10.1007/s00216-012-5858-1

    Article  PubMed  CAS  Google Scholar 

  34. Talari ACS, Movasaghi Z, Rehman S, ur Rehman I (2015) Raman spectroscopy of biological tissues. Appl Spectrosc Rev 50:46–111. https://doi.org/10.1080/05704928.2014.923902

    Article  CAS  Google Scholar 

  35. Jalbert LE, Elkhaled A, Phillips JJ et al (2017) Metabolic profiling of IDH mutation and malignant progression in infiltrating glioma. Sci Rep 7:srep44792. https://doi.org/10.1038/srep44792

    Article  CAS  Google Scholar 

  36. Reitman ZJ, Yan H (2010) Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 102:932–941. https://doi.org/10.1093/jnci/djq187

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Turcan S, Rohle D, Goenka A et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483. https://doi.org/10.1038/nature10866

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Sasaki M, Knobbe CB, Munger JC et al (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488:656–659. https://doi.org/10.1038/nature11323

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Cuyàs E, Fernández-Arroyo S, Corominas-Faja B et al (2015) Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype. Oncotarget 6:12279–12296

    Article  PubMed  PubMed Central  Google Scholar 

  40. Koivunen P, Lee S, Duncan CG et al (2012) Transformation by the R enantiomer of 2-hydroxyglutarate linked to EglN activation. Nature 483:484. https://doi.org/10.1038/nature10898

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Bralten LBC, Kloosterhof NK, Balvers R et al (2011) IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo. Ann Neurol 69:455–463. https://doi.org/10.1002/ana.22390

    Article  PubMed  CAS  Google Scholar 

  42. Elkhaled A, Jalbert LE, Phillips JJ et al (2012) Magnetic resonance of 2-hydroxyglutarate in IDH1-mutated low-grade gliomas. Sci Transl Med 4:116ra5. https://doi.org/10.1126/scitranslmed.3002796

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Tanahashi K, Natsume A, Ohka F et al (2014) Assessment of tumor cells in a mouse model of diffuse infiltrative glioma by Raman spectroscopy. Biomed Res Int 2014:860241. https://doi.org/10.1155/2014/860241

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bergner N, Medyukhina A, Geiger KD et al (2013) Hyperspectral unmixing of Raman micro-images for assessment of morphological and chemical parameters in non-dried brain tumor specimens. Anal Bioanal Chem 405:8719–8728. https://doi.org/10.1007/s00216-013-7257-7

    Article  PubMed  CAS  Google Scholar 

  45. Krafft C, Kirsch M, Beleites C et al (2007) Methodology for fiber-optic Raman mapping and FTIR imaging of metastases in mouse brains. Anal Bioanal Chem 389:1133–1142. https://doi.org/10.1007/s00216-007-1453-2

    Article  PubMed  CAS  Google Scholar 

  46. Beiko J, Suki D, Hess KR et al (2014) IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection. Neuro-Oncology 16:81–91. https://doi.org/10.1093/neuonc/not159

    Article  PubMed  CAS  Google Scholar 

  47. Wijnenga MMJ, French PJ, Dubbink HJ et al (2018) The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis. Neuro-Oncology 20:103–112. https://doi.org/10.1093/neuonc/nox176

    Article  PubMed  Google Scholar 

  48. Dang L, Yen K, Attar EC (2016) IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol Off J Eur Soc Med Oncol 27:599–608. https://doi.org/10.1093/annonc/mdw013

    Article  CAS  Google Scholar 

  49. Miller JJ, Shih HA, Andronesi OC, Cahill DP (2017) Isocitrate dehydrogenase-mutant glioma: evolving clinical and therapeutic implications. Cancer. https://doi.org/10.1002/cncr.31039

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Funding

Financial support was received from Bundesministerium für Bildung und Forschung (13N13807).

Author information

Author notes

  1. Ortrud Uckermann and Wenmin Yao authors contributed equally to this work.

Authors and Affiliations

  1. Neurosurgery, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    Ortrud Uckermann, Wenmin Yao, Tareq A. Juratli, Elke Leipnitz, Gabriele Schackert & Matthias Kirsch

  2. Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Clinical Sensoring and Monitoring, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    Roberta Galli, Edmund Koch & Gerald Steiner

  3. Neuropathology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany

    Matthias Meinhardt

  4. German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany

    Gabriele Schackert & Matthias Kirsch

  5. CRTD/DFG-Center for Regenerative Therapies Dresden—Cluster of Excellence, TU Dresden, Dresden, Germany

    Matthias Kirsch

Authors
  1. Ortrud Uckermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenmin Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tareq A. Juratli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roberta Galli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elke Leipnitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias Meinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edmund Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gabriele Schackert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gerald Steiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Matthias Kirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gerald Steiner or Matthias Kirsch.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 83 KB)

Supplementary material 2 (PDF 115 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Uckermann, O., Yao, W., Juratli, T.A. et al. IDH1 mutation in human glioma induces chemical alterations that are amenable to optical Raman spectroscopy. J Neurooncol 139, 261–268 (2018). https://doi.org/10.1007/s11060-018-2883-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-018-2883-8

Keywords

Search

Navigation