Huang Jiaqi, Weinstein Stephanie J, Kitahara Cari M, Karoly Edward D, Sampson Joshua N, Albanes Demetrius
Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD, USA.
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD, USA.
Oncotarget. 2017 Jul 31;8(41):70366-70377. doi: 10.18632/oncotarget.19705. eCollection 2017 Sep 19.
Malignant glioma is one of the most lethal adult cancers, yet its etiology remains largely unknown. We conducted a prospective serum metabolomic analysis of glioma based on 64 cases and 64 matched controls selected from Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from collection of baseline fasting serum to diagnosis was nine years (inter-decile range 3-20 years). LC/MS-MS identified 730 known metabolites, and conditional logistic regression models estimated odds ratios for one-standard deviation differences in log-metabolite signals. Forty-three metabolites were associated with glioma at <0.05. 2-Oxoarginine, cysteine, alpha-ketoglutarate, chenodeoxycholate and argininate yielded the strongest metabolite signals and were inversely related to overall glioma risk (0.0065≤<0.0083). Also, seven xanthine metabolites related to caffeine metabolism were higher in cases than in controls (0.017≤<0.042). Findings were mostly similar in high-grade glioma cases, although prominent inversely associated metabolites included the secondary 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 (0.0091≤<0.021). A serum metabolomic profile of glioma identified years in advance of clinical diagnoses is characterized by altered signals in arginine/proline, antioxidant, and coffee-related metabolites. The observed pattern provides new potential leads regarding the molecular basis relevant to etiologic or sub-clinical biomarkers for glioma.
恶性胶质瘤是最致命的成人癌症之一，但其病因在很大程度上仍不清楚。我们基于从α-生育酚、β-胡萝卜素癌症预防（ATBC）研究中选取的64例病例和64例匹配对照，对胶质瘤进行了前瞻性血清代谢组学分析。从采集基线空腹血清到诊断的中位时间为9年（十分位数间距为3 - 20年）。液相色谱/串联质谱法鉴定出730种已知代谢物，条件逻辑回归模型估计了对数代谢物信号一个标准差差异的比值比。43种代谢物与胶质瘤的关联度<0.05。2-氧代精氨酸、半胱氨酸、α-酮戊二酸、鹅去氧胆酸和精氨酸盐产生了最强的代谢物信号，且与总体胶质瘤风险呈负相关（0.0065≤<0.0083）。此外，与咖啡因代谢相关的7种黄嘌呤代谢物在病例组中高于对照组（0.017≤<0.042）。在高级别胶质瘤病例中，研究结果大多相似，尽管显著负相关的代谢物包括次级胆汁酸硫酸甘氨胆酸盐和3β-羟基-5-胆烯酸、外源性硫酸对羟基苯甲酸甲酯、性类固醇5α-孕烷-3β,20β-二醇单硫酸盐以及辅因子/维生素草酸盐（0.0091≤<0.021）。在临床诊断前数年就确定的胶质瘤血清代谢组学特征是精氨酸/脯氨酸、抗氧化剂和咖啡相关代谢物的信号改变。观察到的模式为与胶质瘤病因或亚临床生物标志物相关的分子基础提供了新的潜在线索。
