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

Charleen Adams, Rebecca C Richmond, Diana L Dos Santos Ferreira, Wes Spiller, Vanessa Y Tan, Jie Zheng, Peter Wurtz, Jenny L Donovan, Freddie C Hamdy, David E Neal, J Athene Lane, George Davey Smith, Caroline L Relton, Rosalind A Eeles, Brian E Henderson, Christopher A Haiman, Zsofia Kote-Jarai, Fredrick R Schumacher, Ali Amin Al Olama, Sara BenllochKenneth Muir, Sonja I Berndt, David V Conti, Fredrik Wiklund, Stephen J Chanock, Susan M Gapstur, Victoria L Stevens, Catherine M Tangen, Jyotsna Batra, Judith A Clements, Henrik Grönberg, Nora Pashayan, Johanna Schleutker, Demetrius Albanes, Alicja Wolk, Catharine M L West, Lorelei A Mucci, Geraldine Cancel-Tassin, Stella Koutros, Karina D Sørensen, Lovise Maehle, Ruth C Travis, Robert Hamilton, Sue Ann Ingles, Barry S Rosenstein, Yong-Jie Lu, Graham G Giles, Adam S Kibel, Ana Vega, Manolis Kogevinas, Kathryn L Penney, Jong Y Park, Janet L Stanford, Cezary Cybulski, Borge G Nordestgaard, Hermann Brenner, Christiane Maier, Jeri Kim, Esther M John, Manuel R Teixeira, Susan L Neuhausen, Kim DeRuyck, Azad Razack, Lisa F Newcomb, Davor Lessel, Radka P Kaneva, Nawaid Usmani, Frank Claessens, Paul Townsend, Manuela Gago Dominguez, Monique J Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa A Cannon-Albright, Hardev Pandha, Stephen N Thibodeau, Richard M Martin

Research output: Contribution to journalArticle (Academic Journal)

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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.

Original languageEnglish
Pages (from-to)208-216
Number of pages9
JournalCancer Epidemiology, Biomarkers and Prevention
Volume28
Issue number1
Early online date23 Oct 2018
DOIs
Publication statusPublished - Jan 2019

Structured keywords

  • ICEP
  • Centre for Surgical Research
  • BTC (Bristol Trials Centre)

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  • Projects

    IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

    Gaunt, L. F. & Davey Smith, G.

    1/04/1831/03/23

    Project: Research

    Rework of IEU 2 Relton Programme

    Relton, C. L.

    1/04/1831/03/23

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