Comparative cerebrospinal fluid metabolites profiling in glioma patients to predict malignant transformation and leptomeningeal metastasis with a potential for preventive personalized medicine

Abstract

Glioma shows progression presenting as malignant transformation or leptomeningeal metastasis (LM). However, longitudinal biopsy of brain parenchyma is difficult due to its critical location, whereas cerebrospinal fluid (CSF) can be obtained serially with a little invasiveness of puncture. Thus, if we could find a biomarker for glioma progression, we could predict such event and determine therapeutic interventions as early as possible. In this study, we examined whether cerebrospinal fluid (CSF) metabolome profiles can reflect glioma grade, difference with non-glial tumor, and LM status. We selected 32 CSF samples from glioma patients, and compared them with 10 non-tumor control and seven non-glial brain tumor (medulloblastoma) samples. A total of 10,408 low-mass ions (LMIs) were detected as a candidate of metabolites using mass spectrometry, and representative LMIs were identified via the Human Metabolome Database. Grade IV gliomas showed eight LMIs, including acetic acid, of higher levels (summed sensitivity and specificity > 180%) than grade III gliomas. Grade IV gliomas demonstrated more abundant 30 LMIs, including glycerophosphate, compared with medulloblastoma, but none was mutually exclusive. Phospholipid derivatives were significantly more abundant in LM (−) than LM (+) gliomas regardless of glioma grade. LMIs representative of LM (+) gliomas were derivatives of glycolysis. We also verified discriminative LMIs based on mean expression level of each LMI (Student t test, p < 0.05) and evaluated the differences of the above analyses. Over 90% of metabolite pathways indicated from two analytical models were common to each other. Non-targeted mass spectrometry of CSF metabolites revealed significantly different profiles across gliomas that possibly permitted differentiation between glioma grades, LM, and non-glial brain tumors.

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Abbreviations

CNS:

central nervous system

CSF:

cerebrospinal fluid

HMDB:

Human Metabolome Database

HPLC/MS:

high-performance liquid chromatography/MS

IDH1:

isocitrate dehydrogenase 1

LM:

leptomeningeal metastasis

LMIs:

low-mass ions

LOME:

low-mass-ion discriminant equation

MALDI:

matrix-assisted laser desorption ionization

MS:

mass spectroscopy

ODG:

oligodendroglioma

PA:

phosphatidic acids

PE:

phosphatidylethanolamine

PPPM:

predictive preventive personalized medicine

PS:

phosphatidylserine

TOF:

time-of-flight

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Funding

This work was supported by grants from the National Cancer Center, Korea (NCC-1710871-3, 1910090-1 and 1910294-1), the Korea Health Industry Development Institute of Ministry of Health and Social Welfare, Republic of Korea (H1731340-2), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2017R1A2B4007859).

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Authors

Contributions

BC. Y, JH. L, and H-S. G designed and supervised the study, and analyzed data. JW. K, SH. S, H. Y, and K-Y. L contributed to acquisition of data. JH. I, TH. K, and KH. K contributed to the analysis and interpretation of data. JH. K and JB. P designed the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ho-Shin Gwak.

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The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The study procedure was approved by National Cancer Center and all patients signed consent forms. All CSF samples were obtained after Institutional Review Board (NCC-150002) approval in May 2015; written informed consent was obtained from each participant before the collection. The ethics approval was given in compliance with the Declaration of Helsinki.

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Im, J.H., Yoo, B.C., Lee, J.H. et al. Comparative cerebrospinal fluid metabolites profiling in glioma patients to predict malignant transformation and leptomeningeal metastasis with a potential for preventive personalized medicine. EPMA Journal (2020). https://doi.org/10.1007/s13167-020-00211-4

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Keywords

  • Predictive preventive personalized medicine
  • Cerebrospinal fluid
  • Glioma
  • Grade
  • Leptomeningeal metastasis
  • Metabolome