Abstract 936: Serum lipid metabolites and alpha-ketoglutarate are inversely associated with aggressive prostate cancer

Abstract

Abstract Background: There are very few well-established risk factors for prostate cancer. Metabolomic profiling of blood represents an agnostic approach with the potential to identify biomarkers associated with risk. We previously identified several circulating lipid and energy metabolism-related compounds (e.g., alpha-ketoglutarate; AKG) that were altered in men who later developed prostate cancer. Our aim here was to determine the extent to which those findings replicated in a larger study, and whether new metabolite signals could be uncovered. Methods: We conducted a prospective prostate cancer case-control analysis nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort, and sampled 200 cases (100 aggressive and 100 non-aggressive), matching one control to each based on age and date of baseline fasting serum collection. Median time from serum collection to prostate cancer diagnosis was 10 years (range, 1-20). Sera were analyzed on a high resolution accurate mass (HRAM) platform of ultrahigh performance liquid chromatography/mass spectroscopy (LC-MS) and gas chromatography/mass spectroscopy (GC-MS) (Metabolon, Inc.) that identified 654 known metabolites. Over- and under-representation of metabolite classes among our top metabolite signals was tested using the Fisher's exact test for metabolites jointly classified as having a p-value <0.05 (Y/N) and as belonging to a specific chemical class (Y/N). For each metabolite, we used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) of risk associated with a one standard deviation increment in metabolite concentration. Results: Of the 32 metabolites associated with aggressive prostate cancer at p<0.05, 22 were lipids, which as a metabolite class was strongly associated with aggressive but not non-aggressive prostate cancer risk (p = 3.1 × 10−4 and p = 0.10, respectively) (20 of the 22 lipids were inversely associated with aggressive disease risk). Inositol-1-phosphate and oleoyl-linoleoyl-glycerophosphoinositol-1 were the two strongest metabolite signals for aggressive prostate cancer (OR 0.55, 95% CI 0.37-0.80, p = 0.002; and, OR 0.64, 95% CI 0.47-0.87, p = 0.004, respectively). The AKG association of our earlier study was replicated in the present analysis (OR 0.65, 95% CI 0.47-0.91, p = 0.011). Some steroid and thyroid hormones were positively associated with both aggressive and non-aggressive prostate cancer. Conclusion: In this prospective study, serum lipid metabolites were inversely associated with risk of aggressive prostate cancer, including particularly inositol-1-phosphate and oleoyl-linoleoyl-glycerophosphoinositol-1, and the data confirm our previous finding that men with higher AKG were less likely to develop aggressive prostate cancer. A role for altered energy and lipid metabolism in the pathogenesis of aggressive prostate cancer is implicated. Citation Format: Alison Mondul, Steven Moore, Joshua Sampson, Stephanie Weinstein, Demetrius Albanes. Serum lipid metabolites and alpha-ketoglutarate are inversely associated with aggressive prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 936. doi:10.1158/1538-7445.AM2015-936