Background: Obesity is an established risk factor for advanced prostate cancer. We performed whole body metabolomics profiling in pre-diagnostic blood specimens to identify metabolites associated with risk of advanced prostate cancer, and assess the extent to which obesity modifies this association.

Methods: Our study was nested within the prospective US Health Professionals Follow-up Study during the study period 1993 and 2014. We selected 212 advanced prostate cancer (≥ stage T3b, distant metastasis or cancer death during follow-up) patients and 212 matched controls for whom pre-diagnostic bloods were collected with a median 5.5 years prior to diagnosis. Metabolomics profiling was performed at the Broad Institute using liquid chromatography-tandem mass spectrometry to assay 295 known metabolites. We estimated odds ratios and 95% confidence intervals using multivariable conditional logistic regression to examine associations of individual metabolites and cancer risk. We also performed pathway analyses using a method adapted from gene set enrichment analysis to identify metabolite classes associated with advanced prostate cancer.

Results: We identified 29 circulating metabolites in pre-diagnostic bloods that were significantly associated with advanced prostate cancer risk. These metabolites included carnitines and phospholipids, diacylglycerols (DAG) and triacylglycerols (TAG). Using pathway analyses, we found metabolites in DAG and TAG pathways were highly significantly (FDR<10-8) enriched in men with advanced prostate cancer. 166 of the 295 metabolites were significantly (p<0.001) associated with obesity. When we stratified by a man’s obesity status, we observed unique metabolomics profiles associated with advanced prostate cancer. Circulating amines (including carnitines) were associated with advanced prostate cancer in overweight men while lipid metabolites (including DAGs and TAGs) were associated with advanced cancer in the healthy weight men.

Conclusion: Altered levels of TAG and DAG metabolites in prediagnostic bloods are strongly associated with an increased risk of advanced prostate cancer, independent of obesity. The finding that circulating lipids were specifically associated with advanced prostate cancer in healthy weight patients suggests there are men with normal body mass index but who are metabolically obese. The specific lipid metabolite classes enriched in advanced prostate cancer support the hypothesis that obesity acts through dysregulation of liver fatty acid metabolism rather than through metabolic actions of the adipose tissue itself.

Citation Format: Lorelei A. Mucci, Ericka Ebot, Clary Clish, Sarah Markt, Renea Taylor, Matthew Watt, Philip Kantoff, Edward Giovanucci, Matthew VAnder Heiden, Kathryn Wilson. Amine and lipid metabolites are enriched in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2498. doi:10.1158/1538-7445.AM2017-2498