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

• DOI: 10.1016/j.euf.2021.12.002
• Publication Date: 2022-03-11T21:57:14Z
• Authors: 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
• Keywords: SDHB; SDHA; SDHD; Fumarase

Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes.To define compare the genomic metabolomic hallmarks SDHRCC FHRCC.We analyzed FHRCC tumors with either immunohistochemical evidence protein expression or genomically confirmed biallelic inactivation SDHA/B/C/D/AF2 FH.Somatic alterations were identified using clinical pipelines, allele-specific copy number (CNAs) FACETS. Mass spectrometry-based profiling was performed on available tumors.Tumors for 42 patients (25 FHRCC, 17 SDHRCC). In germline analysis, 16/17 SDHRCCs harbored a alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic FH variants. lower mutation burden (p = 0.02) CNA 0.0002) than FHRCCs. All presented deletion chromosome 1p (overlapping SDHB), demonstrated high but not ubiquitous 1q (FH locus). Both exhibited significant idiopathic accumulation metabolite guanine. elevated levels urea metabolites (argininosuccinate, citrulline, fumarate), elevation numerous acylcarnitines. These characteristic metabolic changes allowed identification previously unrecognized SDH-deficient RCC.Despite sharing similar genetic etiology, represent distinct molecular entities unique abnormalities.Kidney gene encoding succinate dehydrogenase hydratase enzyme rare. We sought to features these cancer entities.