Targeted Quantification of Carbon Metabolites Identifies Metabolic Progression Markers and an Undiagnosed Case of SDH-Deficient Clear Cell Renal Cell Carcinoma in a German Cohort
Doreen William,
Kati Erdmann,
Jonas Ottemöller,
Anastasios Mangelis,
Catleen Conrad,
Mirko Peitzsch,
Evelin Schröck,
Graeme Eisenhofer,
Aristeidis Zacharis,
Susanne Füssel,
Daniela Aust,
Barbara Klink,
Susan Richter
Affiliations
Doreen William
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases Partner Site Dresden (NCT/UCC), 01307 Dresden, Germany
Kati Erdmann
German Cancer Consortium (DKTK), 01307 Dresden, Germany
Jonas Ottemöller
Department of Urology, Technische Universität Dresden, 01307 Dresden, Germany
Anastasios Mangelis
School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 9NH, UK
Catleen Conrad
Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty Carl Gustav Carus, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Mirko Peitzsch
Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty Carl Gustav Carus, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Evelin Schröck
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases Partner Site Dresden (NCT/UCC), 01307 Dresden, Germany
Graeme Eisenhofer
Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty Carl Gustav Carus, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Aristeidis Zacharis
Department of Urology, Technische Universität Dresden, 01307 Dresden, Germany
Susanne Füssel
German Cancer Consortium (DKTK), 01307 Dresden, Germany
Daniela Aust
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases Partner Site Dresden (NCT/UCC), 01307 Dresden, Germany
Barbara Klink
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases Partner Site Dresden (NCT/UCC), 01307 Dresden, Germany
Susan Richter
Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty Carl Gustav Carus, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Renal cell carcinoma (RCC) is among the 10 most common cancer entities and can be categorised into distinct subtypes by differential expression of Krebs cycle genes. We investigated the predictive value of several targeted metabolites with regards to tumour stages and patient survival in an unselected cohort of 420 RCCs. Unsupervised hierarchical clustering of metabolite ratios identified two main clusters separated by α-ketoglutarate (α-KG) levels and sub-clusters with differential levels of the oncometabolite 2-hydroxyglutarate (2HG). Sub-clusters characterised by high 2HG were enriched in higher tumour stages, suggesting metabolite profiles might be suitable predictors of tumour stage or survival. Bootstrap forest models based on single metabolite signatures showed that lactate, 2HG, citrate, aspartate, asparagine, and glutamine better predicted the cancer-specific survival (CSS) of clear cell RCC patients, whereas succinate and α-ketoglutarate were better CSS predictors for papillary RCC patients. Additionally, this assay identifies rare cases of tumours with SDHx mutations, which are caused predominantly by germline mutations and which predispose to development of different neoplasms. Hence, analysis of selected metabolites should be further evaluated for potential utility in liquid biopsies, which can be obtained using less invasive methods and potentially facilitate disease monitoring for both patients and caregivers.
