Pre-diagnostic metabolite concentrations and prostate cancer risk in 1077 cases and 1077 matched controls in the European Prospective Investigation into Cancer and Nutrition


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Julie Schmidt1,Georgina Fenson1,Sabina Rinaldi2,Augustin Scalbert2,Paul Appleby1,David Achaintre2,Marc Gunter2,Pietro Ferrari2,Timothy Key1,Ruth Travis1
1University of Oxford,2International Agency for Research on Cancer



Little is known about how pre-diagnostic metabolites in blood relate to prostate cancer risk. We aimed to investigate the prospective association between plasma metabolite concentrations and risk of prostate cancer overall, and by time to diagnosis and tumour characteristics, and risk of prostate cancer death.


In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic plasma concentrations of 122 metabolites were measured using targeted mass spectrometry (AbsoluteIDQ p180 Kit) and compared between 1077 prostate cancer cases and 1077 matched controls.  Prostate cancer risk associated with metabolite concentrations was estimated by multivariable conditional logistic regression, and multiple testing was accounted for using a false discovery rate controlling procedure.


Seven metabolite concentrations, i.e. acylcarnitine C18:1, amino acids citrulline and trans-4-hydroxyproline, glycerophospholipids PC aa C28:1, PC ae C30:0 and PC ae C30:2, and sphingolipid SM (OH) C14:1, were associated with prostate cancer (p<0.05) but none of the associations were statistically significant after controlling for multiple testing. Citrulline was associated with a decreased risk of prostate cancer (OR1SD=0.73; 95%CI 0.62-0.86; ptrend=0.0002) in the first five years of follow-up after taking multiple testing into account, but not after longer follow-up; results for other metabolites did not vary by time to diagnosis. After controlling for multiple testing, 12 glycerophospholipids were inversely associated with advanced stage disease, with risk reduction up to 46% per standard deviation increase in concentration (OR1SD=0.54; 95% CI 0.40-0.72; ptrend=0.00004 for PC aa C40:3). Death from prostate cancer was associated with seven metabolites from various classes.


Several metabolites, i.e. C18:1, citrulline, trans-4-hydroxyproline, three glycerophospholipids and SM (OH) C14:1, might be related to prostate cancer. Analyses by time to diagnosis indicated that citrulline may be a marker of subclinical prostate cancer while other metabolites might be related to aetiology. Several glycerophospholipids were inversely related to advanced stage disease.