Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep 18;8(60):101203-101214.
doi: 10.18632/oncotarget.20983. eCollection 2017 Nov 24.

Cerebrospinal fluid metabolomic profiles can discriminate patients with leptomeningeal carcinomatosis from patients at high risk for leptomeningeal metastasis

Byong Chul Yoo  1 , Jun Hwa Lee  1 , Kyung-Hee Kim  1 , Weiwei Lin  2 , Jong Heon Kim  2 , Jong Bae Park  2 , Hyun Jin Park  3 , Sang Hoon Shin  4 , Heon Yoo  4 , Ji Woong Kwon  4 , Ho-Shin Gwak  2   4
Affiliations

Cerebrospinal fluid metabolomic profiles can discriminate patients with leptomeningeal carcinomatosis from patients at high risk for leptomeningeal metastasis

Byong Chul Yoo et al. Oncotarget. .

Abstract

Purpose: Early diagnosis of leptomeningeal carcinomatosis (LMC) is necessary to improve outcomes of this formidable disease. However, cerebrospinal fluid (CSF) cytology is frequently false negative. We examined whether CSF metabolome profiles can be used to differentiate patients with LMC from patients having a risk for development of LMC.

Results: A total of 10,905 LMIs were evaluated using PCA-DA. The LMIs defined Group 2 with a sensitivity of 85% and a specificity of 91%. After selecting 33 LMIs, including diacetylspermine and fibrinogen fragments, the CSF metabolomics profile had a sensitivity of 100% and a specificity of 93% for discriminating Group 1b from the other groups. After selecting 21 LMIs, including phosphatidylcholine, the CSF metabolomics profile differentiated LMC (Group 2) patients from the high-risk groups of Group 3 and Group 4 with 100% sensitivity and 100% specificity.

Materials and methods: We prospectively collected CSF from five groups of patients: Group 1a, systemic cancer; Group 1b, no tumor; Group 2, LMC; Group 3, brain metastasis; Group 4, brain tumor other than brain metastasis. All metabolites in the CSF samples were detected as low-mass ions (LMIs) using mass spectrometry. Principal component analysis-based discriminant analysis (PCA-DA) and two search algorithms were used to select the LMIs that differentiated the patient groups of interest from controls.

Conclusions: Analysis of CSF metabolite profiles could be used to diagnose LMC and exclude patients at high-risk of LMC with a 100% accuracy. We expect a future validation trial to evaluate CSF metabolic profiles supporting CSF cytology.

Keywords: cerebrospinal fluid; diagnosis; leptomeningeal carcinomatosis; metabolome; profile.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST None.

Figures

Figure 1
Figure 1. Separation results using PCA-DA with all LMIs
(A) Group 1b vs. groups of 1a/2/3/4. (B) Group 2 vs. groups of 1a/3/4.
Figure 2
Figure 2. Separation results with discriminative LMIs
(A) Group 1b vs. groups of 1a/2/3/4 (LOME 1-33). (B) Group 2 vs. groups of 1a/3/4 (LOME 2-21).
Figure 3
Figure 3. Identification of CSF metabolic peptides in LOME 1-33
MS and MS/MS spectra of CSF metabolites with 768.8542 m/z (A-a) and 777.3360 m/z (B-a). MS and MS/MS pattern analyses were performed using a Triple TOF 5600+ mass spectrometer. Peptide sequence analysis of CSF metabolites with 768.8542 m/z (A-b) and 777.3360 m/z (B-b). Identification of 768.8542 m/z (A-c) and 777.3360 m/z (B-c) as fibrinogen alpha (ADSGEGDFLAEGGGVR) and beta (QGVNDNEEGFFSAR) fragments, respectively.
Figure 3
Figure 3. Identification of CSF metabolic peptides in LOME 1-33
MS and MS/MS spectra of CSF metabolites with 768.8542 m/z (A-a) and 777.3360 m/z (B-a). MS and MS/MS pattern analyses were performed using a Triple TOF 5600+ mass spectrometer. Peptide sequence analysis of CSF metabolites with 768.8542 m/z (A-b) and 777.3360 m/z (B-b). Identification of 768.8542 m/z (A-c) and 777.3360 m/z (B-c) as fibrinogen alpha (ADSGEGDFLAEGGGVR) and beta (QGVNDNEEGFFSAR) fragments, respectively.
Figure 4
Figure 4. Differential CSF levels of fibrinogen alpha/beta chain, N1, N12-diacetylspermine, and phosphatidylcholine in five different groups
Normalized peak area (arbitrary unit) represents relative amounts of identified metabolites in CSF. Fibrinogen alpha/beta chain (A and B) and N1, N12-diacetylspermine (C) are one of the components in LOME 1-33; phosphatidylcholine (D) is in LOME 2-21.
Figure 4
Figure 4. Differential CSF levels of fibrinogen alpha/beta chain, N1, N12-diacetylspermine, and phosphatidylcholine in five different groups
Normalized peak area (arbitrary unit) represents relative amounts of identified metabolites in CSF. Fibrinogen alpha/beta chain (A and B) and N1, N12-diacetylspermine (C) are one of the components in LOME 1-33; phosphatidylcholine (D) is in LOME 2-21.
Figure 5
Figure 5. Search algorithm II
(A) Germination module. (B) Growth module. (C) Shrinkage module.
See this image and copyright information in PMC

References

    1. Debus OM, Lerchl A, Bothe HW, Bremer J, Fiedler B, Franssen M, Koehring J, Steils M, Kurlemann G. Spontaneous central melatonin secretion and resorption kinetics of exogenous melatonin: a ventricular CSF study. J Pineal Res. 2002;33:213–7. - PubMed
    1. Frankfort SV, Tulner LR, van Campen JP, Verbeek MM, Jansen RW, Beijnen JH. Amyloid beta protein and tau in cerebrospinal fluid and plasma as biomarkers for dementia: a review of recent literature. Curr Clin Pharmacol. 2008;3:123–31. - PubMed
    1. Romeo MJ, Espina V, Lowenthal M, Espina BH, Petricoin EF, 3rd, Liotta LA. CSF proteome: a protein repository for potential biomarker identification. Expert Rev Proteomics. 2005;2:57–70. - PubMed
    1. Diez B, Balmaceda C, Matsutani M, Weiner HL. Germ cell tumors of the CNS in children: recent advances in therapy. Childs Nerv Syst. 1999;15:578–85. - PubMed
    1. Nakagawa H, Kubo S, Murasawa A, Nakajima S, Nakajima Y, Izumoto S, Hayakawa T. Measurements of CSF biochemical tumor markers in patients with meningeal carcinomatosis and brain tumors. J Neurooncol. 1992;12:111–20. - PubMed