Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study
Authors: Adams Charleen D. , Richmond Rebecca , Ferreira Diana L. Santos , Spiller Wes , Tan Vanessa , Zheng Jie , Würtz Peter , Donovan Jenny , Hamdy Freddie , Neal David , Lane J. Athene , Smith George Davey , Relton Caroline , Eeles Rosalind A. , Haiman Christopher A. , Kote-Jarai ZSofia , Schumacher Fredrick R. , Olama Ali Amin Al , Benlloch Sara , Muir Kenneth , Berndt Sonja I. , Conti David V. , Wiklund Fredrik , Chanock Stephen J. , Gapstur Susan , Stevens Victoria L. , Tangen Catherine M. , Batra Jyotsna , Clements Judith A. , Gronberg Henrik , Pashayan Nora , Schleutker Johanna , Albanes Demetrius , Wolk Alicja , West Catharine M.L. , Mucci Lorelei A. , Cancel-Tassin Géraldine , Koutros Stella , Sorensen Karina Dalsgaard , Maehle Lovise , Travis Ruth C. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry S. , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Vega Ana , Kogevinas Manolis , Penney Kathryn L. , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Brenner Hermann , Maier Christiane , Kim Jeri , John Esther M. , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka P. , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Dominguez Manuela Gago , Roobol Monique J. , Menegaux Florence , Khaw Kay-Tee , Cannon-Albright Lisa A. , Pandha Hardev , Thibodeau Stephen N. , Martin Richard M. 
Published: October 2018

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 &lt; 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.