Endocrine Abstracts

Recent discoveries in mutations in TCA cycle enzymes; succinate dehydrogenase (SDH), fumarate hydratase (FH), iso-citrate dehydrogenase (IDH) and malate dehydrogenase MDH2, have reinforced the link between mitochondrial dysfunction and cancer¹. Phaeochromocytoma and paraganglioma (PPGL) are now recognised to be the most heritable tumour, with 40%¹ having a genetic defect. Mutations in the SDH genes are the most frequently implicated genetic abnormality in hereditary PPGL and are also implicated in the development of wild type GIST tumours. The aim of this study was to evaluate the translational utility of ex vivo metabolomics profiling of PPGL and GIST tumours by HRMAS ¹H NMR spectroscopy. HRMAS ¹H NMR data acquisition was performed on 30 fresh frozen tumour samples (26 PPGL and 4 GIST). Absolute metabolite concentrations were estimated by fitting the metabolite signals in the water-suppressed HRMAS ¹H NMR spectrum in LCModel and using tissue water signal as internal standard for absolute concentration². The lactate, glutamate and glycero-phosphocholine (GPC) concentrations were significantly lowered in SDH mutated tumours compared to wild type (WT) tumour tissues, whereas succinate was several folds higher in SDH mutated tumours tissues. A cut off of greater than 0.61 mmol/l was established to distinguish between SDH mutated tumours and wild type or other hereditary causes of PPGL, with a sensitivity of 95% and specificity of 100% on ROC curve analysis. Significantly lower lactate indicates down regulation of glycolysis in SDH mutated tumours compared to WT tumours. Lowered glutamate, aspartate and choline containing compounds (GPC and t-Choline) indicates reduced amino-acid and membrane phospholipid metabolism in SDH mutated tumours. These key differences in the metabolomic fingerprint of SDH mutated tumours suggests specific metabolic vulnerability and requires further investigation to determine if this vulnerability can be exposed for therapeutic intervention. One paraganglioma sample was detected to have 2 hydroxyglutarate (2HG) accumulation and subsequent genetic sequencing identified a somatic IDH1 (R132C) mutation in the PGL. Detection of succinate accumulation in a single wild type GIST tumour was relevant in determining the pathogenicity of a novel SDHA variant, identified in the germline of that patient.

References: 1. Mercado-Asis LB, Wolf KI, Jochmanova I, Taïeb D. Phaeochomocytoma a genetic and diagnostic update. Endocr Pract. 2018 24 (1) 78–90. doi: 10.4158/EP-2017-0057. Epub 2017 Nov 16.

2. Madhu B, et al. Response of Degarelix treatment in human prostate cancer monitored by HR-MAS ¹H NMR spectroscopy. Metabolomics 2016 12 120.