• Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
• Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland Ohio.
• Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.
• Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
• Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. sharifn@ccf.org.

BACKGROUND: Diet and the gut microbiome have a complex interaction that generates metabolites with an unclear effect on lethal prostate cancer (PCa) risk. Identification of modifiable risk factors for lethal PCa is challenging given the long natural history of this disease and difficulty of prospectively identifying lethal cancers.

METHODS: Mass spectrometry was performed on baseline serum samples collected from 173 lethal PCa cases and 519 controls enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial. Baseline serum levels of choline, carnitine, betaine, γ-butyrobetaine, crotonobetaine, phenylacetylglutamine, hippuric acid, and p-cresol sulfate were quantified and analyzed by quartile. Conditional multivariable logistic regression analysis associated analyte levels with lethal PCa incidence after adjusting for BMI and PSA. The Cochran-Armitage test evaluated analyte level trends across quartiles.

RESULTS: Relative to those in the first quartile, cases with the highest baseline levels of choline (Q4 OR: 2.19, 95% CI: 1.23-3.90; P-trend: 0.005) and betaine (Q4 OR: 1.86, 95% CI: 1.05-3.30; P-trend: 0.11) exhibited increased odds of developing lethal PCa. Higher baseline serum levels of phenylacetylglutamine (Q4 OR: 2.55, 95% CI: 1.40-4.64; P-trend: 0.003), a gut-microbiome metabolite of phenylalanine with adrenergic activity, were also associated with lethal PCa.

CONCLUSIONS: Baseline serum levels of one-carbon methyl donors and adrenergic compounds resulting from human and gut-microbiota-mediated metabolism are associated with increased lethal PCa risk.

IMPACT: Dietary composition, circulating metabolite levels, and downstream signaling pathways may represent modifiable risk factors associated with incident lethal PCa. Beta-adrenergic blockade represents an additional target for oncologic risk reduction.