Metabolomic Urine Profile: Searching for New Biomarkers of SDHx-Associated Pheochromocytomas and Paragangliomas

Abstract

Context Metabolomic studies of pheochromocytoma and paraganglioma tissue showed a correlation between metabolomic profile and presence of SDHx mutations, especially a pronounced increase of succinate. Objective To compare the metabolomic profile of 24-hour urine samples of SDHx mutation carriers with tumors (affected mutation carriers), without tumors (asymptomatic mutation carriers), and patients with sporadic pheochromocytomas and paragangliomas. Methods Proton nuclear magnetic resonance spectroscopic profiling of urine samples and metabolomic analysis using pairwise comparisons were complemented by metabolite set enrichment analysis to identify meaningful patterns. Results The urine of the affected SDHx carriers showed substantially lower levels of seven metabolites than the urine of asymptomatic mutation carriers (including, succinate and N-acetylaspartate). The urine of patients with SDHx-associated tumors presented substantially higher levels of three metabolites compared with the urine of patients without mutation; the metabolite set enrichment analysis identified gluconeogenesis, pyruvate, and aspartate metabolism as the pathways that most probably explained the differences found. N-acetylaspartate was the only metabolite the urinary levels of which were significantly different between the three groups. Conclusions The metabolomic urine profile of the SDHx mutation carriers with tumors is different from that of asymptomatic carriers and from that of patients with sporadic neoplasms. Differences are likely to reflect the altered mitochondria energy production and pseudohypoxia signature of these tumors. The urinary levels of N-acetylaspartate and succinate contrast with those reported in tumor tissue, suggesting a defective washout process of oncometabolites in association with tumorigenesis. The role of N-acetylaspartate as a tumor marker for these tumors merits further investigation.

Significance of Alpha-inhibin Expression in Pheochromocytomas and Paragangliomas

“…The SDHx-related disease is associated with distinct metabolome and methylome profiles [45][46][47][48][49] ; however, HIF-2α is activated in both VHL-related and SDHx-related tumors, whereas HIF-1α is differentially expressed in the VHL-related glycolytic pathway. 50 Although we could not examine the cellular mechanisms of INHA upregulation, coexpression of alpha-inhibin in both SDHx-related and VHL-related tumors suggest that HIF-2α mediates this process in PPGLs.…”

Succinate dehydrogenase and MYC-associated factor X mutations in pituitary neuroendocrine tumours

“…Metabolomics has predominantly been applied to tumour tissue. Its application to liquid biopsy and the possibility of obtaining rapid results on urine or blood to detect accumulated metabolites circulated from SDHx-related tumours could change future clinical practice (Martins, et al 2019). However, further data and understanding of the peripheral metabolomics signatures of heterozygous carriers versus affected patients must be developed before the technique can be routinely implemented in the clinical setting.…”