Prospective serum metabolomic profiling of lethal prostate cancer

Abstract

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.

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

“…In contrast, little is known about the association of lysophosphatidylcholines (treelet component 3) with risk of dying from prostate cancer. Another study in ATBC reported an inverse association between lysolipid 1‐linoleoyl‐glycerophosphatidylcholine (18:2), which is comparable to lysoPC a C18:2 included in TC3 of the current study, and risk of death from prostate cancer ( n deaths = 523), but death was not an outcome in the other previous papers.…”

“…Previously, relatively small prospective studies ( n cases = 74–1,077), including our study in the European Prospective Investigation into Cancer and Nutrition (EPIC), showed that men with higher circulating concentrations of lipids and/or energy‐related metabolites might have lower risk of prostate cancer, especially more aggressive tumor subtypes . Moreover, a prospective study of lethal prostate cancer reported associations with metabolites in redox (inverse), dipeptide (positive), pyrimidine (mostly positive) and gamma‐glutamyl amino acid (positively) pathways ( n deaths = 523) . These studies mostly had limited power and have primarily investigated individual metabolites, which do not capture patterns in the metabolite profile reflecting correlations among metabolites; such patterns might represent metabolites which are part of the same metabolic pathway or originating from the same dietary sources .…”

“…[6][7][8][9] Moreover, a prospective study of lethal prostate cancer reported associations with metabolites in redox (inverse), dipeptide (positive), pyrimidine (mostly positive) and gamma-glutamyl amino acid (positively) pathways (n deaths = 523). 10 These studies mostly had limited power and have primarily investigated individual metabolites, which do not capture patterns in the metabolite profile reflecting correlations among metabolites 11 ; such patterns might represent metabolites which are part of the same metabolic pathway 12 or originating from the same dietary sources. 13 To overcome this and the issue of multiple testing, dimension-reduction methods such as treelet transform can be applied.…”

An Update on the Prognostic and Predictive Serum Biomarkers in Metastatic Prostate Cancer

“…Subsequently, Huang et al conducted a large prospective serum metabolomic analysis of lethal prostate cancer in 523 cases and 523 controls [ 50 ]. Thirty-four serum metabolites were associated with death from prostate cancer.…”

Applications of Metabolomics in Forensic Toxicology and Forensic Medicine

“…In other unclear circumstances, the cause and mechanism of death can be explained by a novel research method that can be described as “metabolomics autopsy”, showing undiscovered pathophysiological mechanisms in different death causes. Metabolic profiling of post-mortal biological specimens may explain more deeply the pathogenesis of fatal disorders like cardiovascular disease [ 67 ], fatal cancers [ 68 , 69 ], diabetes mellitus [ 70 ], or traumatic brain injury [ 71 ]. On the other hand, important disturbances in selected metabolic pathways leading to changes in the concentration of the indicated metabolites may constitute a significant extension of the postmortem diagnosis, especially associated with stages of the disease.…”