Abstract 3224: Prospective serum metabolomic profiling of fatal prostate cancer

Abstract

Abstract Metabolic dysregulation may play a role in the etiology of fatal prostate cancer, yet the association with pre-diagnostic serum metabolites has not been elucidated. We conducted a prospective serum metabolomic analysis of fatal prostate cancer risk in 523 cases and 523 matched controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from baseline fasting serum collection to prostate cancer death was 18 years (interdecile range 10-26 years). We profiled 860 known metabolites through an ultrahigh-performance LC-MS/MS platform, and conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals of risk associated with 1-standard deviation increases in the log-metabolite signals. Based on a false discovery rate (FDR) of 0.15 or lower, 34 metabolites are identified as being associated with fatal prostate cancer. Notably, increased serum thioproline and the three cysteine-related amino acids combined (thioproline, cysteine and cystine) are associated with lower odds of fatal disease (OR=0.75 and 0.71, respectively; P≤8.2×10-5). In contrast, the serum dipeptide leucylglycine (OR=1.36, P=8.2×10-5), and three gamma-glutamyl amino acids, including gamma-glutamylvaline, gamma-glutamylglycine and gamma-glutamylleucine (OR=1.28-1.30, P≤4.6×10-4), are associated with increased fatal disease risk. Several other dipeptides including histidylalanine, valylglycine and leucylglutamine, as well as the nucleotides dihydroorotate, pseudouridine, 2'-O-methyluridine, 5,6-dihydrouridine and 5-methyluridine (ribothymidine), also have significant positive associations with fatal disease risk. Findings are not materially altered by adjustment for body mass index, smoking, serum total and HDL cholesterol, serum alpha-tocopherol and retinol, or the ATBC trial supplementation. Our results are also similar across strata of time from blood collection to prostate cancer death and age at blood collection. Gene-set analysis (GSA) reveals a significant peptide super-metabolic pathway association with lethal disease (P<0.0001), and the sub-pathways of dipeptides, pyrimidines (uracil containing), gamma-glutamyl amino acids, glycine/serine/threonine, n3 and n6 polyunsaturated fatty acids, amino-sugars, androgenic steroids, dicarboxylate fatty acids, and endocannabinoids are similarly associated with fatal prostate cancer (FDRs ≤ 0.1). Our study demonstrates a serum risk profile up to two decades prior to death of prostate cancer that is characterized by multiple dysregulated biochemical metabolites of redox status and dipeptide, pyrimidine (uracil), and gamma-glutamyl amino acid metabolism. The findings represent novel leads related to the molecular basis of the etiology or subclinical course of fatal prostate cancer that warrant examination in other populations. Citation Format: Jiaqi Huang, Alison M. Mondul, Stephanie J. Weinstein, Andriy Derkach, Steven C. Moore, Joshua N. Sampson, Demetrius Albanes. Prospective serum metabolomic profiling of fatal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3224.