SDHC – Gastrointestinal Stromal Tumor

SDHC encodes the C subunit of mitochondrial complex II, and its inactivation defines a distinct subset of succinate dehydrogenase‐deficient gastrointestinal stromal tumors (gastrointestinal stromal tumor). These tumors lack KIT and PDGFRA mutations, present predominantly in gastric locations with epithelioid or mixed morphology, and often exhibit multifocal growth and indolent but recurrent behavior.

Germline loss-of-function variants in SDHC have been identified in Carney-Stratakis syndrome, an autosomal dominant condition characterized by GIST and paraganglioma. In an international series of 11 patients from 7 unrelated families, 3 carried SDHC truncating or splice variants (e.g., c.288dup (p.Glu97Ter)) segregating with disease in at least 8 affected individuals across pedigrees (PMID:17667967).

In pediatric and adolescent cases, SDHC germline mutations manifest with additional cystic lesions beyond GIST. An adolescent male with bilateral renal and neck cysts harbored an SDHC frameshift variant and an SDH‐deficient GIST, underscoring the need for germline testing in wild-type GISTs for surveillance implications (PMID:30301441).

A subset of SDH-deficient GISTs without detectable coding variants exhibits SDHC promoter hypermethylation. Targeted sequencing of 59 dSDH GISTs revealed SDHC epimutations in 15 of 16 SDHx-wild-type tumors, with concordant loss of SDHC mRNA and protein expression, supporting an epigenetic mechanism of gene silencing (PMID:25540324).

Functional studies demonstrate that SDHC inactivation, via mutation or epimutation, leads to succinate accumulation, reactive oxygen species generation, and pseudohypoxic signaling. Yeast models carrying SDHC‐equivalent Arg72 substitutions show abolished complex II activity and increased superoxide production, linking SDHC loss to oncogenic pathways (PMID:17636259).

Integration of genetic and experimental data establishes a robust association between SDHC alterations and SDH-deficient GIST. Immunohistochemical loss of SDHB/SDHC is a reliable triage tool to identify patients for genetic and epigenetic testing. Early recognition of SDHC issues informs prognosis, guides surveillance for syndromic features, and supports genetic counseling.

Key Take-home: SDHC loss through germline mutation or promoter hypermethylation is a validated driver of a distinct SDH-deficient GIST subtype, with direct implications for diagnosis, familial risk assessment, and management.

References

• European Journal of Human Genetics • 2008 • Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. PMID:17667967
• Science Translational Medicine • 2014 • Recurrent epimutation of SDHC in gastrointestinal stromal tumors. PMID:25540324
• Pediatric and Developmental Pathology • 2019 • Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor With SDHC Germline Mutation and Bilateral Renal and Neck Cysts. PMID:30301441
• 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

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