Minimally invasive metabolomics reveals a distinct uveal melanoma metabolic phenotype

Abstract Background Uveal Melanoma (UM) micro-metastases can be present prior to diagnosis and relapse after treatment. Earlier detection resulted in an increased incidence of small (T1 and T2) tumors allowing for novel eye-preserving treatment strategies, but reducing available tumor tissue needed for prognostic genomic profiling. Thus, creating the need for minimal-invasive detection and novel prognostication methods. We determined whether tumor presence can be confirmed using metabolite patterns in blood plasma and evaluated if these patterns differ between high risk (BRCA1-associated protein-1, BAP1), intermediate risk (Splicing Factor 3b Subunit 1, SF3B1) and low risk (Eukaryotic Translation Initiation Factor 1A X-Linked, EIF1AX) mutated tumors. Methods In this retrospective observational study, samples of UM-patients in a discovery (n = 53) and replication (n = 42) set were compared to unaffected control-participants (n = 46) as well as across mutation-based subgroups. Peripheral blood plasma was collected prior to treatment. Metabolite profiles of patients and control-participants were generated as mass/charge (m/z) features using ultra-high performance liquid chromatography mass-spectrometry. After normalization, discriminatory feature patterns were determined using a random forest classifier and a leave-one-out cross-validation procedure. Results We detected differential metabolic patterns between UM-patients and control-participants with a sensitivity of 0.95 and 0.90 and a specificity of 0.98 and 0.98 in the positive and negative ion modes, respectively. Overall, the performance of the model for classifying the subgroups was insufficient in both the positive (merged dataset F1 scores: BAP1: 0.64, SF3B1: 0.37, and EIF1AX: 0.35) and negative (merged dataset F1 scores: BAP1: 0.60, SF3B1: 0.32, and EIF1AX: 0.36) ion modes, respectively. Pathway analysis using annotated metabolites indicated upregulation of tRNA charging, and glycine usage for the creatine biosynthesis. Purine ribonucleosides degradation and the super pathway of citrulline metabolism were downregulated in UM-patients. An increased salvage of bases or decreased purine degradation could indicate a higher energy consumption. Conclusion Minimally-invasive metabolomics has the potential to allow for minimally invasive screening as it distinguishes metabolite patterns, that are putatively associated with oncogenic processes, in peripheral blood derived plasma of UM-patients from control-participants at the time of diagnosis.