Dataset Information

SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response.

ABSTRACT: Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare RCC subtype that is caused by biallelic mutation of one of the four subunits of the SDH complex (SDHA, B, C, and D) and results in inactivation of the SDH enzyme. Here we describe a case of genetically characterized SDH-deficient RCC caused by biallelic (germline plus somatic) SDHA mutations. SDHA pathogenic variants were detected using comprehensive genomic profiling and SDH absence was subsequently confirmed by immunohistochemistry. Very little is known regarding the genomic context of SDH-deficient RCC. Interestingly we found genomic amplifications commonly observed in RCC but there was an absence of additional variants in common cancer driver genes. Prior to genetic testing a PD-1 inhibitor treatment was administered. However, following the genetic results a succession of tyrosine kinase inhibitors were administered as targeted treatment options and we highlight how the genetic results provide a rationale for their effectiveness. We also describe how the genetic results benefited the patient by empowering him to adopt dietary and lifestyle changes in accordance with knowledge of the mechanisms of SDH-related tumorigenesis.

SUBMITTER: McEvoy CR

PROVIDER: S-EPMC5871886 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response.

McEvoy Christopher R CR Koe Lisa L Choong David Y DY Leong Huei San HS Xu Huiling H Karikios Deme D Plew Jeffrey D JD Prall Owen W OW Fellowes Andrew P AP Fox Stephen B SB

NPJ precision oncology 20180320

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare RCC subtype that is caused by biallelic mutation of one of the four subunits of the SDH complex (SDHA, B, C, and D) and results in inactivation of the SDH enzyme. Here we describe a case of genetically characterized SDH-deficient RCC caused by biallelic (germline plus somatic) SDHA mutations. SDHA pathogenic variants were detected using comprehensive genomic profiling and SDH ab ...[more]

PMID: 29872718

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Project description: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.

Dataset Information

SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response.

Publications

SDH-deficient renal cell carcinoma associated with biallelic mutation in succinate dehydrogenase A: comprehensive genetic profiling and its relation to therapy response.

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