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Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study

Adams CD 1 , Richmond R 2 , Ferreira DLS 2 , Spiller W 2 , Tan V 2 , Zheng J 2 Show all authors , Würtz P 3 , Donovan J 4 , Hamdy F 5 , Neal D 5 , Lane JA 4 , Smith GD 2 , Relton C 2 , Eeles RA 6 , Haiman CA 7 , Kote-Jarai Z 6 , Schumacher FR 8 , Olama AAA 9 , Benlloch S 6 , Muir K 10 , Berndt SI 11 , Conti DV 7 , Wiklund F 12 , Chanock SJ 11 , Gapstur S 13 , Stevens VL 13 , Tangen CM 14 , Batra J 15 , Clements JA 15 , Gronberg H 12 , Pashayan N 16 , Schleutker J 17 , Albanes D 11 , Wolk A 18 , West CML 19 , Mucci LA 20 , Cancel-Tassin G 21 , Koutros S 11 , Sorensen KD 22 , Maehle L 23 , Travis RC 24 , Hamilton RJ 25 , Ingles SA 7 , Rosenstein BS 26 , Lu YJ 27 , Giles GG 28 , Kibel AS 29 , Vega A 30 , Kogevinas M 31 , Penney KL 32 , Park JY 33 , Stanford JL 34 , Cybulski C 35 , Nordestgaard BG 36 , Brenner H 37 , Maier C 38 , Kim J 39 , John EM 40 , Teixeira MR 41 , Neuhausen SL 42 , De Ruyck K 43 , Razack A 44 , Newcomb LF 34 , Lessel D 45 , Kaneva RP 46 , Usmani N 47 , Claessens F 48 , Townsend PA 49 , Dominguez MG 50 , Roobol MJ 51 , Menegaux F 52 , Khaw KT 53 , Cannon-Albright LA 54 , Pandha H 55 , Thibodeau SN , Martin RM 2 , PRACTICAL consortium

Affiliations 

  • 1 MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom. chaadams@coh.org
  • 2 MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom
  • 3 Research Programs Unit, Diabetes and Obesity, University of Helsinki and Nightingale Health Ltd., Helsinki, Finland
  • 4 University of Bristol, Bristol, United Kingdom
  • 5 Nuffield Department of Surgical Sciences, University of Oxford and Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
  • 6 The Institute of Cancer Research, London, United Kingdom
  • 7 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
  • 8 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio
  • 9 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom
  • 10 Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, United Kingdom
  • 11 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland
  • 12 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  • 13 Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
  • 14 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 15 Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia
  • 16 University College London, Department of Applied Health Research, London, United Kingdom
  • 17 Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland
  • 18 Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 19 Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, Manchester NIHR Biomedical Research Centre, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom
  • 20 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 21 CeRePP, Tenon Hospital, Paris, France
  • 22 Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
  • 23 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 24 Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, Oxford, United Kingdom
  • 25 Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
  • 26 Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
  • 27 Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, United Kingdom
  • 28 Cancer Epidemiology & Intelligence Division, The Cancer Council Victoria, Melbourne, Victoria, Australia
  • 29 Division of Urologic Surgery, Brigham and Women's Hospital, Boston, Massachusetts
  • 30 Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain
  • 31 Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain
  • 32 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts
  • 33 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida
  • 34 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 35 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 36 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 37 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 38 Institute for Human Genetics, University Hospital Ulm, Ulm, Germany
  • 39 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
  • 40 Cancer Prevention Institute of California, Fremont, California
  • 41 Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal
  • 42 Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California
  • 43 Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Gent, Belgium
  • 44 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 45 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 46 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University, Sofia, Bulgaria
  • 47 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
  • 48 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
  • 49 Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester, United Kingdom
  • 50 Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saúde, SERGAS, Santiago De Compostela, Spain
  • 51 Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 52 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  • 53 Clinical Gerontology Unit, University of Cambridge, Cambridge, United Kingdom
  • 54 Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah
  • 55 The University of Surrey, Guildford, Surrey, United Kingdom
Cancer Epidemiol Biomarkers Prev, 2019 Jan;28(1):208-216.
PMID: 30352818 DOI: 10.1158/1055-9965.EPI-18-0079

Abstract

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).

METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.

RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.

CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.

IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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