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BACKGROUND: The gene fusion and loss are two of the most common somatic molecular alterations in prostate cancer. Here, we investigated the association of prediagnostic-circulating metabolomics and prostate cancer defined by ERG or PTEN status to improve understanding of these etiologically distinct molecular prostate cancer subtypes.METHODS: The study was performed among 277 prostate cancer cases with ERG status, 211 with PTEN status, and 294 controls nested in the Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS). We profiled 223 polar and non-polar metabolites using LC-MS in prediagnostic plasma specimens. We applied enrichment analysis and multinomial logistic regression models to identify biological metabolite classes and individual metabolites associated with prostate cancer defined by ERG or PTEN status.RESULTS: Compared with noncancer controls, sphingomyelin (: 0.01), ceramide (: 0.04), and phosphatidylethanolamine (: 0.03) circulating levels were enriched among ERG-positive prostate cancer cases. Sphingomyelins (: 0.02), ceramides (: 0.005), and amino acids (: 0.02) were enriched among tumors exhibiting PTEN-loss; unsaturated diacylglycerols (: 0.003) were enriched among PTEN-intact cases; and unsaturated triacylglycerols were enriched among both PTEN-loss (: 0.001) and PTEN-intact (: 0.0001) cases. Although several individual metabolites identified in the above categories were nominally associated with ERG or PTEN-defined prostate cancer, none remained significant after accounting for multiple testing.CONCLUSIONS: The molecular process of prostate carcinogenesis may be distinct for men with different metabolomic profiles.IMPACT: These novel findings provide insights into the metabolic environment for the development of prostate cancer.