Urinary Metabolite Signatures Stratify Survival in Malignant Mesothelioma: A Noninvasive Prognostic Tool

Malignant mesothelioma is a rare, aggressive cancer with limited treatment options and few robust prognostic biomarkers. Existing blood-based assays (MESOMARK, fibulin-3, osteopontin) are constrained by inconsistent sensitivity and preanalytical instability. We evaluated four urinary metabolites previously associated with prognosis in lung cancer and intrahepatic cholangiocarcinoma: creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate (CS), and 27-nor-5beta-cholestane-3alpha,7alpha,12alpha,24,25-pentol (cholestane pentol, CP). Metabolites were measured in a clinically annotated mesothelioma cohort (n=95; NCT01950572) with paired RNA-sequencing data. All four correlated positively with a validated 48-gene poor-prognosis expression signature, and a standardized composite of the four showed the strongest concordance (Spearman R=0.34, p=0.001). Overall survival declined progressively with the number of elevated metabolites, and patients with all four elevated had the poorest survival (log-rank p less than 0.0001). Stratifying the composite score by quartile and by median reproduced this graded effect (p less than 0.0001 for both), and associations were independent of age, sex, and disease site. Urinary metabolite profiling offers a simple, repeatable, noninvasive prognostic tool that complements existing blood-based assays and may support risk stratification, longitudinal monitoring, and clinical-trial enrichment in mesothelioma.