Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes.
To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC.
We analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH.
Somatic alterations were identified using clinical pipelines, with allele-specific copy number alterations (CNAs) identified using FACETS. Mass spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors.
Tumors were analyzed for 42 patients (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCCs harbored a germline alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic germline FH variants. SDHRCCs had a lower mutation burden (p = 0.02) and CNA burden (p = 0.0002) than FHRCCs. All SDHRCCs presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCCs demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCCs and FHRCCs exhibited significant idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines. These characteristic metabolic changes allowed identification of a previously unrecognized SDH-deficient RCC.
Despite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities.
Kidney cancers driven by loss of the gene encoding either the succinate dehydrogenase or fumarate hydratase enzyme are rare. We sought to define and compare the genetic and metabolic features of these cancer entities.
European urology focus. 2022 Mar 11 [Epub ahead of print]
Angela Yoo, Cerise Tang, Mark Zucker, Kelly Fitzgerald, Renzo G DiNatale, Phillip M Rappold, Kate Weiss, Benjamin Freeman, Chung-Han Lee, Nikolaus Schultz, Robert Motzer, Paul Russo, Jonathan Coleman, Victor E Reuter, Ying-Bei Chen, Maria I Carlo, Anthony J Gill, Ritesh R Kotecha, A Ari Hakimi, Ed Reznik
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; SUNY Downstate Health Sciences University, Brooklyn, NY, USA; Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Medicine, New York, NY, USA., Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sydney Medical School, University of Sydney, Sydney, Australia; Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St. Leonards, Australia., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: ., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: ., Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: .