Cerebrospinal fluid (CSF) encompasses the tissues of the central nervous system and is routinely collected for diagnosis and monitoring of patients with malignant gliomas and other neurological disorders. However, little is known about the metabolic composition of the CSF and how its constituents may change during treatment. Here, we used a targeted mass spectrometry–based metabolomics platform using selected reaction monitoring to profile the relative levels of more than 200 polar metabolites present in the CSF. We analyzed the metabolic profiles from 10 patients with newly diagnosed or recurrent malignant gliomas and from 7 control patients who do not have any malignancy. We then carried out multiple unbiased forms of classification using a series of computational techniques including unsupervised hierarchical clustering and principal component analysis and identified metabolic signatures that distinguished patients with malignant gliomas from controls. Specific metabolites that correlated with survival include pantothenate, N6-Acetyl-L-lysine (P = 0.0521), N-acetyl-glutamine (P = 0.0417), and acetyllysine (P = 0.0120); those that correlated with tumor size as measured by T1-gadolinium MRI include myoinositol (P = 0.015), kynurenic acid (P = 0.0271), and cholesteryl sulfate (P = 0.0079); and those that correlated with tumor size as measured by fluid attenuated inversion recovery MRI included myoinositol (P = 0.0045), hexose-phosphate (P = 0.0254), cytidine (P = 0.0378), and aminoadipic acid (P = 0.0390). Together, our results provide the first global assessment of the metabolic composition in CSF that accompanies malignancy in the brain, and our results demonstrate that high throughput mass spectrometry technology may have suitable predictive capabilities for the identification of metabolite biomarkers and the segregation of malignant gliomas from controls. This research was supported in part by 3P30CA006516-45S7, P01 CA120964, American Cancer Society fellowship, and A Reason To Ride research fund.
Locasale, JW; Melman, T; Song, SS; Yang, X; Swanson, KD; Cantley, LC; Asara, JM; Wong, ET; Adams, S; Braidy, N; Teo, C; Guillemin, G; Philippe, M; Carole, C; David, T; Eric, G; Isabelle, N-M; de Paula Andre, M; Marylin, B; Olivier, C; L'Houcine, O; Dominique, F-B; Leukel, P; Seliger, C; Vollmann, A; Jachnik, B; Bogdahn, U; Hau, P; Liu, X; Kumar, VBS; McPherson, CM; Chow, L; Kendler, A; Dasgupta, B; Piya, S; White, E; Klein, S; Jiang, H; Lang, F; Alfred Yung, WK; Gomez-Manzano, C; Fueyo, J; Vartanian, A; Guha, A; Fenton, KE; Abdelwahab, M; Scheck, AC; Guo, D; Reinitz, F; Youssef, M; Hong, C; Nathanson, D; Akhavan, D; Kuga, D; Amzajerdi, AN; Soto, H; Zhu, S; Babic, I; Iwanami, A; Tanaka, K; Gini, B; DeJesus, J; Lisiero, DD; Huang, T; Prins, R; Wen, P; Robbins, HI; Prados, M; DeAngelis, L; Mellinghoff, I; Mehta, M; James, CD; Chakravarti, A; Cloughesy, T; Tontonoz, P; Mischel, P; Phillips, J; Mukherjee, J; Cowdrey, C; Wiencke, J; Pieper, RO; Bachoo, R; Marin-Valencia, I; Cho, S; Rakheja, D; Hatanpaa, K; Mashimo, T; Vemireddy, V; Kapur, P; Good, L; Sun, X; Pascual, J; Takahashi, M; Togao, O; Raisanen, J; Maher, EA; DeBerardinis, R; Malloy, C; Choi, C; Mathews, D; Madden, C; Mickey, B; Zheng, S; Ronen, S; Park, I; Jalbert, LE; Ito, M; Ozawa, T; Phillips, JJ; Vigneron, DB; Ronen, SM; Nelson, SJ
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