Pre-diagnostic Serum Metabolomic Profiling of Prostate Cancer Survival

Impaired metabolism may play a role in the development and lethality of prostate cancer, yet a comprehensive analysis of the interrelationships appears lacking. We measured 625 metabolites using ultrahigh performance liquid chromatography/mass spectrometry (LC-MS) and gas chromatography/mass spectrometry (GC-MS) of prediagnostic serum from 197 prostate cancer cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (ages at diagnosis, 55-86 years). Cox proportional hazards models estimated associations between circulating metabolites and prostate cancer mortality for 1 SD differences (log-metabolite scale), adjusted for age, year of diagnosis, and disease stage. Associations between metabolite chemical classes and survival were examined through pathway analysis, and Cox models assessed the relationship with a sterol/steroid metabolite principal component analysis factor score. Elevated serum N-oleoyl taurine was significantly associated with prostate cancer-specific mortality (hazard ratios [HR] = 1.72 per 1 SD, p<.00008, Bonferroni-corrected threshold = 0.05/625; HR = 3.6 for highest vs lowest tertile, p<.001). Pathway analyses revealed a statistically significant association between lipids and prostate cancer death (p<.006, Bonferroni-corrected threshold = 0.05/8), and sterol/steroid metabolites showed the strongest chemical sub-class association (p=.0014, Bonferroni-corrected threshold = 0.05/45). In the principal component analysis, a 1-SD increment in the sterol/steroid metabolite score increased the risk of prostate cancer death by 46%. Prediagnostic serum N-oleoyl taurine and sterol/steroid metabolites were associated with prostate cancer survival.