SDHC – Succinate Dehydrogenase Complex Subunit C and Renal Cell Carcinoma

Succinate dehydrogenase complex subunit C (SDHC) functions as an anchoring component of mitochondrial complex II, linking the tricarboxylic acid cycle to the respiratory chain. Germline variants in SDHC have been implicated in hereditary paraganglioma syndrome type 3 (PGL3) and, less commonly, in renal cell carcinoma (RCC) as part of syndromic tumor predisposition. Evidence from familial studies supports a tumor suppressor role for SDHC in renal epithelium, with loss of function (LoF) leading to oncometabolite accumulation, epigenetic dysregulation, and proliferative signalling.

Genetic evidence for SDHC in RCC arises from two unrelated families. In a PGL3 kindred, a start‐codon variant c.3G>A (p.Met1Ile) was identified in a proband with a carotid body tumor and in his mother with clear cell and papillary RCC; both tumors exhibited somatic loss of heterozygosity at SDHC (PMID:22351710). More recently, an intronic SDHC variant causing aberrant splicing and premature truncation was found in four affected siblings with paragangliomas and RCC, with haplotype evidence for a founder allele (PMID:33195952).

Segregation analysis demonstrates cosegregation of SDHC pathogenic variants with RCC or related neoplasms in five additional relatives across these families, consistent with an autosomal dominant inheritance pattern and two‐hit mechanism (PMID:22351710; PMID:33195952). No conflicting reports have been published to date.

The variant spectrum in RCC includes start‐codon disruptions (e.g., c.3G>A (p.Met1Ile)) and deep intronic splice‐creating mutations. These LoF alleles are consistent with biallelic inactivation in tumors, leading to succinate accumulation and pseudohypoxic signalling. Population‐specific founder alleles have been documented for splicing variants.

Functional studies in Saccharomyces cerevisiae demonstrate that tumor‐associated SDHC missense changes at conserved residues (e.g., p.Arg72Gly and p.Arg72Cys) severely reduce ubiquinone reductase activity, elevate superoxide production, and cause succinate build‐up, supporting a LoF tumour suppressor mechanism (PMID:17636259). Epigenomic profiling of SDH‐deficient RCCs further reveals a CpG island methylator phenotype that may serve diagnostic and therapeutic biomarker roles (PMID:36455002).

Integrating genetic and experimental data yields a ClinGen Moderate level of evidence for SDHC in RCC: six probands across two families, segregation in five relatives, concordant functional assays, and tumor methylation signatures. Additional large‐scale RCC cohorts and in vivo models would strengthen the association.

Key Take-home: Germline SDHC LoF variants confer an autosomal dominant predisposition to RCC via a two‐hit tumor suppressor mechanism, with diagnostic and biomarker potential in CIMP-positive tumors.

References

• Endocrine-related cancer • 2012 • Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3 PMID:22351710
• Journal of the Endocrine Society • 2020 • Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient Paragangliomas PMID:33195952
• The Journal of Biological Chemistry • 2007 • Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate PMID:17636259
• PLoS One • 2022 • Kidney tumors associated with germline mutations of FH and SDHB show a CpG island methylator phenotype (CIMP) PMID:36455002

Evidence Based Scoring (AI generated)