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 language | English (US) |
---|---|
Pages (from-to) | 208-216 |
Number of pages | 9 |
Journal | Cancer Epidemiology Biomarkers and Prevention |
Volume | 28 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2019 |
ASJC Scopus subject areas
- Epidemiology
- Oncology
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Circulating metabolic biomarkers of screen-detected prostate cancer in the ProtecT study'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Circulating metabolic biomarkers of screen-detected prostate cancer in the ProtecT study. / PRACTICAL Consortium.
In: Cancer Epidemiology Biomarkers and Prevention, Vol. 28, No. 1, 01.2019, p. 208-216.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Circulating metabolic biomarkers of screen-detected prostate cancer in the ProtecT study
AU - PRACTICAL Consortium
AU - Adams, Charleen D.
AU - Richmond, Rebecca
AU - Santos Ferreira, Diana L.
AU - Spiller, Wes
AU - Tan, Vanessa
AU - Zheng, Jie
AU - Würtz, Peter
AU - Donovan, Jenny
AU - Hamdy, Freddie
AU - Neal, David
AU - Lane, J. Athene
AU - Smith, George Davey
AU - Relton, Caroline
AU - Eeles, Rosalind A.
AU - Haiman, Christopher A.
AU - Kote-Jarai, ZSofia
AU - Schumacher, Fredrick R.
AU - Olama, Ali Amin Al
AU - Benlloch, Sara
AU - Muir, Kenneth
AU - Berndt, Sonja I.
AU - Conti, David V.
AU - Wiklund, Fredrik
AU - Chanock, Stephen J.
AU - Gapstur, Susan
AU - Stevens, Victoria L.
AU - Tangen, Catherine M.
AU - Batra, Jyotsna
AU - Clements, Judith A.
AU - Gronberg, Henrik
AU - Pashayan, Nora
AU - Schleutker, Johanna
AU - Albanes, Demetrius
AU - Wolk, Alicja
AU - West, Catharine M.L.
AU - Mucci, Lorelei A.
AU - Cancel-Tassin, Géraldine
AU - Koutros, Stella
AU - Sorensen, Karina Dalsgaard
AU - Maehle, Lovise
AU - Travis, Ruth C.
AU - Hamilton, Robert J.
AU - Ingles, Sue Ann
AU - Rosenstein, Barry S.
AU - Lu, Yong Jie
AU - Giles, Graham G.
AU - Kibel, Adam S.
AU - Vega, Ana
AU - Kogevinas, Manolis
AU - Thibodeau, Stephen N.
N1 - Funding Information: P. Wurtz is an employee of and has ownership interest in Nightingale Health Ltd. R.A. Eeles reports receiving speakers bureau honoraria from Janssen. N. Usmani reports receiving commercial research funding from Best Medical and is a consultant/advisory board member for Bayer, Amgen, and Astellas. P. Townsend reports receiving speakers bureau honoraria from MedLabs; is named as an inventor in patents unrelated to this manuscript; is a consultant/advisory board member for DeepMed, NED, and is a scientific advisor for Aptamer Group; and receives shares/license fees from Karus Therapeutics Ltd., Pentagon Biotechnology Ltd, and PRECignature Ltd. No potential conflicts of interest were disclosed by the other authors.This work was supported by Cancer Research UK (CRUK; C18281/A19169) and the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MRC) and the University of Bristol (MC_UU_12013/2; author C. Adams). R.C. Richmond is supported by CRUK (C18281/A19169) and MRC (MC_UU_12013/2). W. Spiller is supported by MRC (MC_UU_12013/1) and a Wellcome Trust studentship (108902/15/Z). V.Y. Tan is supported by CRUK (C18281/A19169). P. Wurtz is funded by the Academy of Finland (grant nos: 312476 and 312477). D.E. Neal is funded by (C11043/A4286, C18281/A8145, and C18281/A11326). J.A. Lane is supported by CRUK (C18281/A19169). C.L. Relton is supported by MRC (MC_UU_12013/2) and CRUK (C18281/A19169). R.A. Eeles is supported by CRUK (C5047/A17528). Z. Kote-Jarai is supported by CRUK (C5047/A17528). K.-T. Khaw with EPIC Norfolk is supported by grants from the MRC (MR/N003284/1; G1000143) and CRUK (14136). R.C. Travis is supported by CRUK (C8221/A19170), CRUK (14136 for EPIC-Norfolk and C570/A16491 for EPIC-Oxford), and the MRC (1000143 for EPIC-Norfolk and MR/M012190/1 for EPIC-Oxford. R.M. Martin is supported by CRUK (C18281/ A19169). The National Institute for Health Research Biomedical Research Centre supported R.M. Martin, C.L. Relton, G.D. Smith. Genotyping of the OncoArray was funded by the US NIH [U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I]. Additional analytic support was provided by NIH NCI U01 CA188392 (principal investigator: F.R. Schumacher). The PRACTICAL consortium was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, European Commission's Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175), and The NIH Cancer Post-Cancer GWAS initiative grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Funding Information: NIH Cancer Post-Cancer GWAS initiative grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Funding Information: This work was supported by Cancer Research UK (CRUK; C18281/A19169) and the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MRC) and the University of Bristol (MC_UU_12013/2; author C. Adams). R.C. Richmond is supported by CRUK (C18281/A19169) and MRC (MC_UU_12013/2). W. Spiller is supported by MRC (MC_UU_12013/1) and a Wellcome Trust studentship (108902/15/Z). V.Y. Tan is supported by CRUK (C18281/A19169). P. Wurtz is funded by the Academy of Finland (grant nos: 312476 and 312477). D.E. Neal is funded by (C11043/A4286, C18281/A8145, and C18281/A11326). J.A. Lane is supported by CRUK (C18281/A19169). C.L. Relton is supported by MRC (MC_UU_12013/2) and CRUK (C18281/A19169). R.A. Eeles is supported by CRUK (C5047/A17528). Z. Kote-Jarai is supported by CRUK (C5047/A17528). K.-T. Khaw with EPIC Norfolk is supported by grants from the MRC (MR/N003284/1; G1000143) and CRUK (14136). R.C. Travis is supported by CRUK (C8221/A19170), CRUK (14136 for EPIC-Norfolk and C570/A16491 for EPIC-Oxford), and the MRC (1000143 for EPIC-Norfolk and MR/M012190/1 for EPIC-Oxford. R.M. Martin is supported by CRUK (C18281/ A19169). The National Institute for Health Research Biomedical Research Centre supported R.M. Martin, C.L. Relton, G.D. Smith. Genotyping of the OncoArray was funded by the US NIH [U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I]. Additional analytic support was provided by NIH NCI U01 CA188392 (principal investigator: F.R. Schuma-cher). The PRACTICAL consortium was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, European Commission's Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175), and The Funding Information: P. Wurtz is an employee of and has ownership interest in Nightingale Health Ltd. R.A. Eeles reports receiving speakers bureau honoraria from Janssen. N. Usmani reports receiving commercial research funding from Best Medical and is a consultant/advisory board member for Bayer, Amgen, and Astellas. P. Townsend reports receiving speakers bureau honoraria from MedLabs; is named as an inventor in patents unrelated to this manuscript; is a consultant/advisory board member for DeepMed, NED, and is a scientific advisor for Aptamer Group; and receives shares/license fees from Karus Therapeutics Ltd., Pentagon Biotechnology Ltd, and PRE-Cignature Ltd. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: © 2019 American Association for Cancer Research.
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85059928972&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059928972&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-18-0079
DO - 10.1158/1055-9965.EPI-18-0079
M3 - Article
C2 - 30352818
AN - SCOPUS:85059928972
VL - 28
SP - 208
EP - 216
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
SN - 1055-9965
IS - 1
ER -