Prospective serum metabolomic profiling of lethal prostate cancer.
Impaired metabolism may play an important role in the pathogenesis of lethal prostate cancer, yet there is a paucity of evidence regarding the association. We conducted a large prospective serum metabolomic analysis of lethal prostate cancer 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 (maximum 30 years). We identified 860 known biochemicals through an ultrahigh-performance LC-MS/MS platform. Conditional logistic regression models estimated odds ratios (OR) and 95% confidence intervals of risk associated with 1-standard deviation (s.d.) increases in log-metabolite signals. We identified 34 metabolites associated with lethal prostate cancer with a false discovery rate (FDR) < 0.15. Notably, higher serum thioproline, and thioproline combined with two other cysteine-related amino acids and redox metabolites, cystine and cysteine, were associated with reduced risk (1-s.d. OR = 0.75 and 0.71, respectively; p ≤ 8.2 × 10-5 ). By contrast, the dipeptide leucylglycine (OR = 1.36, p = 8.2 × 10-5 ), and three gamma-glutamyl amino acids (OR = 1.28-1.30, p ≤ 4.6 × 10-4 ) were associated with increased risk of lethal prostate cancer. Cases with metastatic disease at diagnosis (n = 179) showed elevated risk for several lipids, including especially the ketone body 3-hydroxybutyrate (BHBA), acyl carnitines, and dicarboxylic fatty acids (1.37 ≤ OR ≤ 1.49, FDR < 0.15). These findings provide a prospective metabolomic profile of lethal prostate cancer characterized by altered biochemicals in the redox, dipeptide, pyrimidine, and gamma-glutamyl amino acid pathways, whereas ketone bodies and fatty acids were associated specifically with metastatic disease.
['Huang|Jiaqi|J|0000-0002-7808-9477', 'Mondul|Alison M|AM|0000-0002-8843-1416', 'Weinstein|Stephanie J|SJ|', 'Derkach|Andriy|A|', 'Moore|Steven C|SC|', 'Sampson|Joshua N|JN|', 'Albanes|Demetrius|D|']
D000596:Amino Acids D014408:Biomarkers, Tumor D016022:Case-Control Studies D002853:Chromatography, Liquid D004311:Double-Blind Method D005227:Fatty Acids D006801:Humans D016015:Logistic Models D008297:Male D055432:Metabolomics D008875:Middle Aged D016017:Odds Ratio D011446:Prospective Studies D011471:Prostatic Neoplasms D012307:Risk Factors D053719:Tandem Mass Spectrometry D024502:alpha-Tocopherol D019207:beta Carotene
metabolomics lethal prostate cancer antioxidants nested case-control