Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking <i>KIT</i> and <i>PDGFRA</i> mutations

TLDR

Carney‑Stratakis syndrome, caused by germline mutations in SDH subunits B, C, or D, predisposes individuals to gastrointestinal stromal tumors and paraganglioma through dysfunction of mitochondrial complex II. The study aimed to assess whether defective cellular respiration contributes to sporadic GISTs that lack KIT or PDGFRA mutations. Thirty‑four KIT‑/PDGFRA‑wild‑type GISTs were screened for germline SDH mutations, and tumors without such mutations were examined for SDHB protein expression and complex II activity, with comparisons to KIT‑mutant, NF1‑associated GISTs, and SDH‑deficient paragangliomas. Four of 34 wild‑type GISTs carried germline SDHB or SDHC mutations, and those lacking somatic SDH alterations showed loss or marked reduction of SDHB protein and decreased complex II activity, whereas KIT‑mutant tumors retained SDHB expression; these findings underscore SDH dysregulation as a central oncogenic driver in wild‑type GIST and support routine germline SDH testing.

Abstract

Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1-associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.