SDHB – SDHB-related Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms of the digestive tract, most commonly driven by activating mutations in KIT or PDGFRA. A distinct subset of KIT/PDGFRA-wild-type GISTs exhibits loss of succinate dehydrogenase (SDH) complex activity, marked by absent SDHB immunohistochemical staining and accumulation of succinate ([PMID:25741136]). Germline mutations in the SDHB gene (HGNC:10681) define this SDH-deficient GIST subgroup, often occurring in the setting of Carney-Stratakis dyad with paragangliomas.

Autosomal-dominant inheritance of SDHB variants confers predisposition to SDH-deficient GISTs. In seven unrelated families, eight probands harbor heterozygous SDHB germline mutations with somatic loss of the wild-type allele in tumor tissue, confirming a two-hit mechanism ([PMID:17667967]). No additional affected relatives with disease have been observed, consistent with incomplete penetrance.

Case series further illustrate the phenotypic and molecular spectrum of SDHB-related GISTs. A duodenal SDH-deficient GIST in a 29-year-old man carried the nonsense variant c.268C>T (p.Arg90Ter) with SDHB loss and LOH in tumor cells ([PMID:28324028]). Additional reports describe gastric spindle cell sarcomas and dedifferentiated GISTs with SDHB missense and frameshift mutations, reinforcing the association.

The variant repertoire includes stop-gain and frameshift mutations (e.g., c.268C>T (p.Arg90Ter), c.291_292del (p.Ile97MetfsTer21)), which lead to truncated SDHB proteins and absent complex II activity. Immunohistochemistry for SDHB is a reliable screening tool, with 100% of SDHB-mutant GISTs showing negative staining, whereas KIT/PDGFRA-mutant tumors remain SDHB-positive ([PMID:22160509]).

Functional studies confirm that SDHB loss abolishes complex II enzymatic activity and shifts tumor metabolism toward glycolysis. SDHB knockout models exhibit succinate accumulation, hypoxia-inducible factor stabilization, and epigenetic alterations consistent with human SDH-deficient GIST biology ([PMID:22835832]). Riboflavin and demethylating agents have been explored to rescue mitochondrial function in preclinical systems.

Integration of genetic and experimental evidence supports a Strong clinical validity classification for the SDHB–GIST association, with definitive molecular mechanism and diagnostic immunohistochemical assays. Germline SDHB testing is indicated for all KIT/PDGFRA-wild-type GISTs to guide surveillance and familial risk assessment. Key take-home: SDHB germline variants cause autosomal-dominant predisposition to SDH-deficient GISTs, detectable by SDHB immunohistochemistry and confirmed by molecular testing.

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]
• Journal of Clinical Endocrinology and Metabolism • 2017 • A Duodenal SDH-Deficient Gastrointestinal Stromal Tumor in a Patient With a Germline SDHB Mutation [PMID:28324028]
• World Journal of Gastroenterology • 2015 • Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors [PMID:25741136]
• Familial Cancer • 2012 • A novel germline SDHB mutation in a gastrointestinal stromal tumor patient without bona fide features of the Carney-Stratakis dyad [PMID:22160509]
• FASEB Journal • 2012 • Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function [PMID:22835832]

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