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BMC Med. 2017 Jul 5;15(1):122. doi: 10.1186/s12916-017-0885-6.

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

Author information

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
International Agency for Research on Cancer, 69372, Lyon, CEDEX 08, France.
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Foundation under Public Law, DE-69120, Heidelberg, Germany.
Department of Epidemiology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, DE-14558, Nuthetal, Germany.
Hellenic Health Foundation, GR-11527, Athens, Greece.
WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, GR-11527, Athens, Greece.
Department of Epidemiology, Harvard T. H. Chan School of Public Health, 02115, Boston, Massachusetts, USA.
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133, Milano, Italy.
Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, 50134, Florence, Italy.
Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin, 10126, Turin, Italy.
CPO-Piemonte, 10126, Turin, Italy.
Cancer Registry and Histopathology Unit, "Civic-M.P.Arezzo" Hospital, ASP 97100, Ragusa, Italy.
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA, Bilthoven, The Netherlands.
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
Public Health Division of Gipuzkoa, Regional Government of the Basque Country, 20014, Donostia-San Sebastián, Spain.
CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.
Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, 18012, Granada, Spain.
Navarra Public Health Institute, 31003, Pamplona, Spain.
Navarra Institute for Health Research (IdiSNA) Pamplona, Pamplona, Spain.
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, 30003, Murcia, Spain.
Public Health Directorate, 33006, Asturias, Spain.
MRC Epidemiology Unit, University of Cambridge, CB2 0SR, Cambridge, UK.
School of Clinical Medicine, University of Cambridge, CB2 2QQ, Cambridge, UK.
Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, 45110, Ioannina, Greece.



Little is known about how pre-diagnostic metabolites in blood relate to risk of prostate cancer. 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 death from prostate cancer.


In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition, pre-diagnostic plasma concentrations of 122 metabolites (including acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose and sphingolipids) were measured using targeted mass spectrometry (AbsoluteIDQ p180 Kit) and compared between 1077 prostate cancer cases and 1077 matched controls. Risk of prostate cancer associated with metabolite concentrations was estimated by multi-variable conditional logistic regression, and multiple testing was accounted for by 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 (odds ratio (OR1SD) = 0.73; 95% confidence interval (CI) 0.62-0.86; p trend = 0.0002) in the first 5 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; p trend = 0.00004 for PC aa C40:3). Death from prostate cancer was associated with higher concentrations of acylcarnitine C3, amino acids methionine and trans-4-hydroxyproline, biogenic amine ADMA, hexose and sphingolipid SM (OH) C14:1 and lower concentration of glycerophospholipid PC aa C42:4.


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. More prospective data are needed to confirm these associations.


Acylcarnitines; Amino acids; Biogenic amines; European Prospective Investigation into Cancer and Nutrition (EPIC); Glycerophospholipids; Hexose; Mass spectrometry; Metabolomics; Prospective study; Prostate cancer risk; Sphingolipids

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