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IDH1 p.R132H ctDNA and D-2-hydroxyglutarate as CSF biomarkers in patients with IDH-mutant gliomas

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Abstract

Introduction

We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas.

Methods

CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images.

Results

The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 of the 9 samples from patients with IDH-mutant glioma, and IDH1 p.R132H mutation was detected in 5 of the 7 samples. The MAF ranged from 0.3 to 39.95%. Total 2HG level, D-2HG level, and D/L-2HG ratio in CSF were significantly higher in patients with IDH-mutant gliomas than in patients with IDH-wildtype gliomas. D-2HG level and D/L-2HG ratio correlated with total tumor volume in patients with IDH-mutant gliomas but not in patients with IDH-wildtype gliomas.

Conclusion

Our results suggest that detection of IDH1 p.R132H mutation by ddPCR and increased D-2HG level in CSF may help identify IDH-mutant gliomas. Our results also suggest that D-2HG level and D/L-2HG ratio correlate with tumor volume in patients with IDH-mutant gliomas. Further prospective studies with larger cohorts are needed to validate these findings.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

2HG:

2-Hydroxyglutarate

cfDNA:

Cell-free DNA

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

ctDNA:

Circulating tumor DNA

D-2HG:

D-enantiomer of 2-hydroxyglutarate

FLAIR:

Fluid-attenuated inversion recovery

IDH1 :

Isocitrate dehydrogenase 1

L-2HG:

L-enantiomer of 2-hydroxyglutarate

MAF:

Mutant allele frequency

MR:

Magnetic resonance

WHO:

World Health Organization

References

  1. Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812. https://doi.org/10.1126/science.1164382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yan H, Parsons W, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 8:765–773

    Article  Google Scholar 

  3. Paschka P, Schlenk RF, Gaidzik VI et al (2010) IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 28:3636–3643. https://doi.org/10.1200/jco.2010.28.3762

    Article  CAS  PubMed  Google Scholar 

  4. Borger DR, Tanabe KK, Fan KC et al (2012) Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncology 17:72–79. https://doi.org/10.1634/theoncologist.2011-0386

    Article  CAS  Google Scholar 

  5. 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  CAS  PubMed  PubMed Central  Google Scholar 

  6. Waitkus MS, Diplas BH, Yan H (2016) Isocitrate dehydrogenase mutations in gliomas. NeuroOncology 18:16–26. https://doi.org/10.1093/neuonc/nov136

    Article  CAS  Google Scholar 

  7. Ye D, Guan K-L, Xiong Y (2018) Metabolism, activity, and targeting of D- and L-2-hydroxyglutarates. Trends Cancer 4:151–165. https://doi.org/10.1016/j.trecan.2017.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bi J, Chowdhry S, Wu S et al (2020) Altered cellular metabolism in gliomas—an emerging landscape of actionable co-dependency targets. Nat Rev Cancer 20:57–70. https://doi.org/10.1038/s41568-019-0226-5

    Article  CAS  PubMed  Google Scholar 

  9. Bettegowda C, Sausen M, Leary RJ et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3007094

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mattos-Arruda LD, Mayor R, Ng CKY et al (2015) Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun 6:8839. https://doi.org/10.1038/ncomms9839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pentsova EI, Shah RH, Tang J et al (2016) Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid. J Clin Oncol 34:2404–2415. https://doi.org/10.1200/jco.2016.66.6487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Miller AM, Shah RH, Pentsova EI et al (2019) Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature 565:654–658. https://doi.org/10.1038/s41586-019-0882-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nakamizo S, Sasayama T, Shinohara M et al (2013) GC/MS-based metabolomic analysis of cerebrospinal fluid (CSF) from glioma patients. J Neuro-Oncology 113:65–74. https://doi.org/10.1007/s11060-013-1090-x

    Article  CAS  Google Scholar 

  14. Kalinina J, Ahn J, Devi NS et al (2016) Selective detection of the D-enantiomer of 2-hydroxyglutarate in the CSF of glioma patients with mutated isocitrate dehydrogenase. Clin Cancer Res 22:6256–6265. https://doi.org/10.1158/1078-0432.ccr-15-2965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Locasale JW, Melman T, Song S et al (2012) Metabolomics of human cerebrospinal fluid identifies signatures of malignant glioma*. Mol Cell Proteomics 11(M111):014688. https://doi.org/10.1074/mcp.m111.014688

    Article  PubMed  Google Scholar 

  16. Takayasu T, Shah M, Dono A et al (2020) Cerebrospinal fluid ctDNA and metabolites are informative biomarkers for the evaluation of CNS germ cell tumors. Sci Rep UK 10:14326. https://doi.org/10.1038/s41598-020-71161-0

    Article  CAS  Google Scholar 

  17. Ballester LY, Lu G, Zorofchian S et al (2018) Analysis of cerebrospinal fluid metabolites in patients with primary or metastatic central nervous system tumors. Acta Neuropathol Commun 6:85. https://doi.org/10.1186/s40478-018-0588-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pirozzi CJ, Yan H (2021) The implications of IDH mutations for cancer development and therapy. Nat Rev Clin Oncol 18:645–661. https://doi.org/10.1038/s41571-021-00521-0

    Article  CAS  PubMed  Google Scholar 

  19. Ye D, Guan K-L, Xiong Y (2018) Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates. Trends Cancer 4:

  20. 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 131:803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  PubMed  Google Scholar 

  21. Amara CS, Ambati CR, Vantaku V et al (2019) Serum metabolic profiling identified a distinct metabolic signature in Bladder Cancer Smokers: a key metabolic enzymes associated with patient survival. Cancer Epidemiol Prev Biomark. https://doi.org/10.1158/1055-9965.epi-18-0936

    Article  Google Scholar 

  22. Sanson M, Marie Y, Paris S et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154. https://doi.org/10.1200/jco.2009.21.9832

    Article  CAS  PubMed  Google Scholar 

  23. Network CGAR, Brat DJ, Verhaak RGW et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. New Engl J Med 372:2481–2498. https://doi.org/10.1056/nejmoa1402121

    Article  Google Scholar 

  24. Soffietti R, Bettegowda C, Mellinghoff IK et al (2022) Liquid biopsy in gliomas: a RANO review and proposals for clinical applications. NeuroOncology. https://doi.org/10.1093/neuonc/noac004

    Article  Google Scholar 

  25. 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  CAS  PubMed  PubMed Central  Google Scholar 

  26. Waitkus MS, Diplas BH, Yan H (2018) Biological role and therapeutic potential of IDH mutations in cancer. Cancer Cell 34:186–195. https://doi.org/10.1016/j.ccell.2018.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mellinghoff IK, Penas-Prado M, Peters KB et al (2021) Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase I trial. Clin Cancer Res 27:4491–4499. https://doi.org/10.1158/1078-0432.ccr-21-0611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mellinghoff IK, Ellingson BM, Touat M et al (2020) Ivosidenib in isocitrate dehydrogenase 1–mutated advanced glioma. J Clin Oncol 38:3398–3406. https://doi.org/10.1200/jco.19.03327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in Neuro-Oncology Working Group. J Clin Oncol 28:1963–1972. https://doi.org/10.1200/jco.2009.26.3541

    Article  PubMed  Google Scholar 

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Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number K08CA241651 and the Brain Cancer SPORE 2P50CA127001 (LYB). The metabolomics core was supported by CPRIT Core Facility Support Award RP170005 (“Proteomic and Metabolomic Core Facility”), NCI Cancer Center Support Grant P30CA125123, NIH/NCI grant R01CA220297, NIH/NCI grant R01CA216426, and intramural funds from the Dan L. Duncan Cancer Center.

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Authors and Affiliations

  1. Vivian L. Smith Department of Neurosurgery McGovern Medical School, The University of Texas Health Science Center, 6431 Fannin Street, Houston, TX, 77030, USA

    Yoko Fujita, Antonio Dono, Juan C. Rodriguez, Jay-Jiguang Zhu & Yoshua Esquenazi

  2. Department of Radiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Luis Nunez-Rubiano & Roy F. Riascos

  3. Department of Pathology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Allison Bellman

  4. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, 1515 Holcombe Blvd., Unit 85, Houston, TX, 77030, USA

    Leomar Y. Ballester

  5. Advanced Technology Core, Metabolomics Core, Baylor College of Medicine, Houston, TX, 77030, USA

    Vasanta Putluri, Abu Hena Mostafa Kamal & Nagireddy Putluri

  6. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Nagireddy Putluri

  7. Memorial Hermann Hospital-TMC, Houston, TX, 77030, USA

    Roy F. Riascos, Jay-Jiguang Zhu & Yoshua Esquenazi

  8. Center for Precision Health, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Yoshua Esquenazi

  9. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, TX, 77030, USA

    Mauli Shah & Leomar Y. Ballester

Authors
  1. Yoko Fujita
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Contributions

Conceptualization: LYB. Sample collection: AD, AB, MS, JCR, JJZ. Data collection and processing: YF, LNR, AHMK, VP, NP, RFR. Statistical analysis: YF, LYB. Interpretations of results: YF, YE, LYB. Manuscript writing: YF. Reviewing and editing: LYB. Critical feedback: all authors. Approval of the final manuscript: all authors.

Corresponding authors

Correspondence to Yoshua Esquenazi or Leomar Y. Ballester.

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Competing interests

The authors declare no competing interests.

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None of the authors has any conflicts to declare.

Ethical approval

The study was approved by the institutional review board at The University of Texas Health Science Center at Houston.

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Informed consent was obtained from all individual participants included in the study.

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Fujita, Y., Nunez-Rubiano, L., Dono, A. et al. IDH1 p.R132H ctDNA and D-2-hydroxyglutarate as CSF biomarkers in patients with IDH-mutant gliomas. J Neurooncol 159, 261–270 (2022). https://doi.org/10.1007/s11060-022-04060-1

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