Pre-diagnostic circulating untargeted metabolomics and risk of overall and clinically significant prostate cancer: A systematic review meta-analysis

Background Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong potential to act as clinical biomarkers. However, evidence of associations between circulating metabolites with overall and clinically significant PCa risk has not been quantitively aggregated.

We performed a systematic review and meta-analysis of untargeted pre-diagnostic circulating metabolomic studies across four clinically distinct outcomes: overall, low- to intermediate-risk, high- to very high-risk, and lethal PCa, each compared to controls.

Twelve studies were identified in the systematic review, and up to 408 metabolites were meta-analyzed across the four PCa outcomes. Three, eleven and nineteen metabolites were significantly associated with risk of overall, high- to very high-risk and lethal PCa, respectively. Metabolites associated with high- to very high-risk PCa were significantly enriched for lipids. Limited evidence of correlation between metabolite effects across outcomes was identified, highlighting potentially unique metabolite drivers of high-risk and lethal PCa. In follow-up analyses, 13 of the significant metabolites were found to be drug and/or dietary modifiable.

These findings suggest the strong potential for metabolites to inform risk of lethal PCa, which could inform risk-stratified screening strategies and facilitate the identification of targets for PCa prevention. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the National Cancer Institute at the National Institutes of Health (R00 CA246063, Pacific Northwest Prostate Cancer SPORE P50 CA097186, Cancer Center Support Grant P30 CA015704), an award from the Andy Hill Cancer Research Endowment Distinguished Researchers Program, a Fred Hutch/University of Washington SPORE Career Enhancement Program award, the Prostate Cancer Foundation (21YOUN11), and the Institute for Prostate Cancer Research. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes This manuscript has been revised to include additional detail on the clinical implications in the discussion Data Availability All data produced in the present work are contained in the manuscript