Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas

Angela Yoo,Paul Russo,Maria I Carlo,Anthony J Gill,Kelly Fitzgerald,Ying-Bei Chen,A Ari Hakimi,Kate Weiss,Mark Zucker,Renzo G Dinatale,Nikolaus Schultz,Phillip M Rappold,Benjamin Freeman,Ed Reznik,Victor E Reuter,Jonathan Coleman,Robert J Motzer ,Christopher S Tang ,Ritesh Kotecha ,Chung‐Han Lee

doi:10.1016/j.euf.2021.12.002

Abstract

BackgroundSuccinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes. ObjectiveTo define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC. Design, setting, and participantsWe 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. Outcome measurements and statistical analysisSomatic 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. Results and limitationsTumors 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. ConclusionsDespite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities. Patient summaryKidney 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.

Highlights

Mutations in protein subunits of succinate dehydrogenase (SDHA/SDHB/SDHC/SDHD and assembly factor SDHAF2) and fumarate hydratase lead to rare forms of renal cell carcinoma (RCC; denoted by SDHRCC and FHRCC, respectively) [1]
RCC patients with a germline FH or SDH mutation are predisposed to developing additional syndromic features; FHRCC patients can develop cutaneous and uterine leiomyomas [9] comprising a genetic syndrome called hereditary leiomyomatosis and RCC (HLRCC); SDHRCC patients have a higher risk of developing pheochromocytomas/paragangliomas [10] and gastrointestinal stromal tumors [11]
We identified 83 RCC patients with a presumed diagnosis of FHRCC or SDHRCC from Memorial Sloan Kettering Cancer Center (MSKCC) and through a multiinstitutional cohort collaboration [14]

Summary

Introduction

Mutations in protein subunits of succinate dehydrogenase (SDHA/SDHB/SDHC/SDHD and assembly factor SDHAF2) and fumarate hydratase (encoded by the single gene FH) lead to rare forms of renal cell carcinoma (RCC; denoted by SDHRCC and FHRCC, respectively) [1]. SDH and FH catalyze consecutive reactions in the tricarboxylic acid (TCA) cycle, and SDH encodes Complex II of the mitochondrial electron transport chain, which is responsible for oxidation of FADH2 [2] Both SDHRCC and FHRCC are rare: it is speculated that SDHRCC constitutes 0.05–0.2% of all RCC diagnoses [3], while FHRCC is comparatively more common but still rare, accounting for 0.5–4.35% of all RCC diagnoses [4]. In vitro data for mouse hepatocyte cell lines with silencing of FH or SDHA suggest that complete loss of either enzyme produces a block in the TCA cycle and consequent accumulation of upstream metabolic intermediates (succinate in SDHRCC and fumarate in FHRCC) [5]. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines

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