Association of Prediagnostic Blood Metabolomics with Prostate Cancer Defined by ERG or PTEN Molecular Subtypes

Abstract

Background: The TMPRSS2: ERG gene fusion and PTEN loss are two of the most common somatic molecular alterations in prostate cancer. Here we investigated the association of pre-diagnostic 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 liquid chromatography-mass spectrometry in pre-diagnostic 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 to non-cancer controls, sphingomyelins (P: 0.01), ceramides (P: 0.04), and phosphatidylethanolamines (P: 0.03) circulating levels were enriched among ERG-positive prostate cancer cases. Sphingomyelins (P: 0.02), ceramides (P: 0.005), and amino acids (P: 0.02) were enriched among tumors exhibiting PTEN-loss; unsaturated diacylglycerols (P: 0.003) were enriched among PTEN-intact cases; unsaturated triacylglycerols were enriched among both PTEN-loss (P: 0.001) and PTEN-intact (P: 0.0001) cases. While 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.