Abstract 2266: A prospective study of serum metabolites and glioma risk

Abstract

Abstract Malignant glioma is one of the most devastating adult malignancies. Although there exists an urgent need for actionable leads regarding its prevention and early detection, the etiology of glioma remains largely unknown. We conducted a prospective serum metabolomic analysis of glioma based on 64 cases and individually matched controls selected from Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from collection of baseline fasting serum to diagnosis of glioma was nine years (interdecile range 3-20 years). We used ultra-high performance LC/MS which identified 730 known metabolites for analysis. Conditional logistic regression models examined odds ratios (ORs) and 95% confidence intervals for one-standard deviation differences in metabolite signals on a log-scale. Forty-three serum metabolites were associated with glioma at P<0.05. 2-Oxoarginine, cysteine, alpha-ketoglutarate, chenodeoxycholate and argininate yielded the strongest metabolite signals and were inversely associated overall risk of glioma (0.0065≤P<0.0083). Three serum acylcarnitines (0.016≤P<0.046), and seven xanthine (i.e., caffeine) metabolites (0.017≤P<0.042) were higher in cases than controls. Findings were mostly similar in high-grade glioma cases, although proportionally more metabolites showed positive risk associations such as N-acetylglutamate, ribonate, and 5-methyluridine (0.04≤P<0.02). Notably, xanthine compounds appeared unrelated to high-grade glioma. Prominent metabolite signals for inverse associations were the bile acids glycocholenate sulfate and 3β-hydroxy-5-cholenoic acid, xenobiotic methyl-4-hydroxybenzoate sulfate, sex steroid 5alpha-pregnan-3beta,20beta-diol monosulfate, and cofactor/vitamin oxalate. We found weaker risk associations for lower-grade glioma, of which none achieved significance at P<0.05. The metabolic sub-pathway analysis revealed associations for primary bile acid, urea cycle/arginine and proline, tocopherol, glycolysis/gluconeogenesis/pyruvate metabolites with overall glioma risk (0.005≤P<0.048); ascorbate and aldarate pathways were associated with high-grade glioma (P=0.02), whereas glycolysis/gluconeogenesis/pyruvate, eicosanoid and glutamate pathways were found to be associated with lower-grade disease (0.01≤P<0.04). These associations did not, however, reach the stringent Bonferroni significance threshold for correction of multiple comparisons. In conclusion, we identified a serum metabolomic profile of glioma, years in advance of clinical diagnoses, characterized by altered molecular signals in the arginine/proline, antioxidant, bile acid, and glycolytic pathways. The observed patterns provide potential new leads regarding the molecular basis relevant to etiologic or sub-clinical biomarkers for glioma. The findings require reexamination in larger and more diverse populations, including through glioma consortia. Citation Format: Jiaqi Huang, Stephanie J. Weinstein, Cari M. Kitahara, Edward Karoly, Joshua N. Sampson, Demetrius Albanes. A prospective study of serum metabolites and glioma risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2266. doi:10.1158/1538-7445.AM2017-2266