SDHA – SDHA-Deficient Gastrointestinal Stromal Tumor

SDHA germline pathogenic variants predispose to a subset of KIT/PDGFRA-wild-type, succinate dehydrogenase (SDH)-deficient gastric gastrointestinal stromal tumors (GISTs) with autosomal dominant inheritance and low penetrance. More than 25 unrelated GIST probands carrying heterozygous SDHA loss-of-function variants—predominantly nonsense and initiation codon changes—have been reported across multiple series (PMID:31413764, PMID:27340750).

Segregation analyses in familial Carney-Stratakis syndrome and other hereditary cohorts identify SDHA variants in affected relatives, though clinical penetrance is incomplete. To date, at least 6 affected family members across multiple kindreds carry SDHA pathogenic variants segregating with GIST or paraganglioma phenotypes (PMID:23109135).

The variant spectrum in SDHA-associated GIST includes initiation codon mutations (e.g., c.1A>C (p.Met1Leu)) and nonsense, splice‐site, and frameshift alterations leading to truncated or absent SDHA protein. Recurrent variants such as p.Arg31Ter and p.Gly453Arg have been documented in independent cohorts, supporting variant pathogenicity (PMID:31413764).

Immunohistochemistry of SDH-deficient GISTs shows concurrent loss of SDHA and SDHB subunit expression, triaging tumors for SDHA genetic testing (PMID:23060355). Functional assays in yeast and Drosophila confirm that SDHA missense and truncating mutations abrogate complex II activity, induce succinate accumulation, and drive pseudo-hypoxia via HIF1α stabilization (PMID:20484225). Magnetic resonance spectroscopy further demonstrates in vivo succinate peaks in SDHx-mutated tumors (PMID:26490314).

Mechanistically, SDHA loss-of-function undermines mitochondrial complex II, leading to oncometabolite accumulation, epigenetic dysregulation, and hypermethylation signatures characteristic of SDH-deficient GISTs. These data support haploinsufficiency as the primary pathogenic mechanism.

References

• Hereditary Cancer Clin Pract • 2019 • Germline c.1A>C heterozygous pathogenic variant in SDHA reported for the first time in a young adult with a gastric gastrointestinal stromal tumour (GIST): a case report PMID:31413764
• Am J Surg Pathol • 2016 • Conventional Risk Stratification Fails to Predict Progression of Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumors: A Clinicopathologic Study of 76 Cases PMID:27340750
• Genes Chromosomes Cancer • 2013 • Overexpression of insulin-like growth factor 1 receptor and frequent mutational inactivation of SDHA in wild-type SDHB-negative gastrointestinal stromal tumors PMID:23109135
• Am J Surg Pathol • 2013 • Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors PMID:23060355
• Hum Mol Genet • 2010 • SDHA is a tumor suppressor gene causing paraganglioma PMID:20484225
• Clin Cancer Res • 2016 • In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma PMID:26490314

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