SUN-349 Prognostic Metabolic Signature in Aggressive Adrenocortical Carcinoma

Abstract

Introduction Adrenocortical carcinoma (ACC) is a rare and aggressive disease with high mortality rate, lack of effective medical therapy, and high recurrence rate even with complete resection. Prognostic biomarkers are needed to guide treatment. The aim of this study was to identify prognostic tissue metabolites and dysregulated pathways to guide treatment. Patients and methods In this study seventeen tumors from patients with advanced metastatic ACC were analyzed through an Ultra High-Performance Liquid Chromatography-Tandem Mass Spectroscopy to detect and identify known and unknown metabolites. Kaplan Meier survival analyses were performed separating patients with high and low levels of each metabolite by median values. A pathway and enrichment analysis utilizing the top 100 small molecules associated with survival was performed through MetaboAnalyst software. Results 841 metabolites were detected. Survival analysis identified 15 metabolites that were prognostic. Eleven known metabolites were identified including N-acetylglutamine, 1-methylhistamine, palmitoyl-linleoyl-glycerol, corticosterone, 2-palmitoyl-GPC, pregnen-diol, androstenediol, and 5,6-dihydrouracil. Three metabolites were found to be independently prognostic in a multivariable analysis: 3-methoxytyrosine (hazard ratio [HR] 36.0, p=0.005), taurocholenate (HR 48.3, p=0.004), and 21-hydroxypregnenolone (HR 7.0, p=0.02). Four adrenocortical steroid synthesis metabolites were significantly different between patients alive vs. dead at the end of follow-up. A pathway and enrichment analysis identified the linoleic acid metabolism pathway to be significantly enriched (p=0.025) with the highest impact coefficient (0.66). Four metabolites in the Linoleic acid pathway were detected: lecithin, linoleic acid, gamma-Linolenic acid and 12,13-dihydroxyoctadec-9-enoic acid (12,13-DiHOME). Among them lecithin, linoleic acid and gamma-Linolenic acid levels were lower while 12,13-DiHOME levels were higher among patients with a higher risk to die of their disease during follow-up (fold change values of 0.73, 0.13, 0.44 and 1.52, respectively). Conclusions In conclusion, an analysis of the tissue metabolome identified a metabolomic signature that was prognostic for overall survival. Furthermore, a metabolomic analysis of adrenocortical carcinoma suggests a pivotal role for the linoleic acid pathway in determining patients’ prognosis.