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Angela Yoo, BA: Disclosure information not submitted.
Introduction: Mutations in TCA cycle enzymes succinate dehydrogenase (SDH) and fumarate hydratase (FH) are associated with rare kidney cancers. However, the molecular features of SDH-deficient RCC (SDHRCC) and FH-deficient RCC (FHRCC) have not been well defined. Using genomic and metabolomic profiling, we aimed to define the genetic and molecular hallmarks of TCA-cycle mutant RCC.
Methods: Patients included met either immunohistochemical (loss of FH/SDH expression and/or 2-succinocysteine positivity) or molecular (biallelic loss of FH or SDHA/B/C/D/AF2) criteria for FH- or SDH- deficiency. Both germline (if available) and somatic information were integrated to determine biallelic status. Somatic variants were identified using standard clinical pipelines, and allele-specific copy number changes were studied using the FACETS algorithm. Mass-spectrometry-based metabolomics was completed on 6 samples (3 SDHRCC and 3 FHRCC).
Results: 37 patients were included, 26 FHRCC and 11 SDHRCC. In the germline analysis, nearly all (16/17) SDHRCC presented with a germline mutation to SDHB, whereas only 12/20 FHRCC had pathogenic FH variants.
FHRCC has a significantly higher tumor mutation burden (p =0.0165, Fig 1a) and fraction of the genome that is copy-number-altered (p = 1e-04, Fig 1b) than SDHRCC. FHRCC often arises with additional somatic mutations (Fig 1c). In contrast, only 2/11 SDHRCC patients had co-occurring mutations (Fig 1d). Notably, 100% of SDHRCC presented with deletion of chromosome 1p (location of SDHB), whereas FHRCC demonstrated high but not universal loss of 1q (FH locus).
Although both FH and SDH loss truncate the TCA cycle, FHRCC and SDHRCC have metabolic differences. Urea cycle metabolites such as argininosuccinate, citrulline, homocitrulline, and arginine were elevated in FHRCC tumors but not SDHRCC tumors. FHRCC also had an excess of N6-succinyladenosine compared to SDHRCC. However, SDHRCC had an elevation of acyl-carnitine compared to FHRCC, suggesting that disruption of FADH2 oxidation through Complex II/SDH may impair normal fatty acid oxidation.
Conclusions: Despite a superficial similarity, FHRCC and SDHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities.
Source of Funding: This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 and the Bryan Bumsted fund