MON-317 Metabolomic signatures of lethal prostate cancer in pre-diagnosis serum samples from the Child Health and Development Studies

Abstract Disclosure: N. Krigbaum: None. X. Hu: None. P.M. Cirillo: None. S. Teeny: None. B. Minasenko: None. Y. Go: None. B. Cohn: None. D.P. Jones: None. Background: Prostate cancer is the second most common cancer in men and the second leading cause of cancer death among men of all races and ethnicities in the United States. While all men are at risk of prostate cancer, Black men have higher risk, are diagnosed at a younger age, have more advanced disease when found, and are twice as likely to die from prostate cancer than other men. Methods: We conducted a prospective Metabolome Wide Association Study (MWAS) of lethal prostate cancer in in 773 Black and 331 non-Black men followed for 60 years in the Child Health and Development Studies (CHDS) cohort. Our sample consisted of 111lethal prostate cancer cases in Black men (median age of 74 at death) and 258 cases in non-Black men (median age of 77 at death). Controls were matched on birthyear (220 Black controls; 515 non-Black controls). We conducted High Resolution Metabolomics (HRM) on pre-diagnostic, archived serum samples collected a median of 34.5 years before diagnosis.Untargeted pathway and metabolite analyses were performed using Rodin (https://github.com/BM-Boris/rodin/tree/main). Feature intensities were log2 transformed to decrease heteroscedasticity. We used Partial Least-Squares Discriminant Analysis (PLS-DA) to identify features that best distinguished between the lethal prostate cancer and control groups and ANOVA was used to test for differential expression. Features with p<0.05 or VIP>2 were used for pathway enrichment analysis with Rodin, using HILIC +ESI.Results: Metabolism of arachidonic acid and prostaglandin were enriched for Black men (raw p-value< .05) and non- Black men (raw p- value < 0.01). Methionine and cysteine metabolism (p-value < .005) and Glutamate metabolism (p-value <.05) were associated with lethal prostate cancer only in Blacks. These pathways suggest oxidative stress pathway signals unique to Black men who later develop fatal prostate cancer.Conclusion: Our prospective study is the first to show shared and race-dependent metabolic signatures associated with future lethal prostate cancer a median of 34.5 years before diagnosis and highlight the importance of oxidative stress defense pathways in Black men years prior to cancer diagnosis. These metabolic signatures can serve as indicators for prognosis and risk of lethality. Experimental studies will be essential to investigate causation and discovery of opportunities for personalized prevention of lethal prostate cancer. Presentation: Monday, July 14, 2025