Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA-activating mutations, but a small subset is associated with loss of function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs by germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSSs); the latter 2 also include paraganglioma as a component. SDH-deficient GISTs were identified in this study on the basis of immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly, all gastric GISTs in patients <20 years, and a substantial percentage of those in patients <40 years, but only rare GISTs in older adults were SDH deficient. There was a female predominance of over 2:1. Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations. SDH-deficient GISTs were often multiple and typically showed plexiform muscularis propria involvement and epithelioid hypercellular morphology. They were consistently KIT-positive and DOG1/Ano 1-positive and almost always smooth muscle actin negative. Tumor size and mitotic activity varied, and the tumors were somewhat unpredictable with low mitotic rates developing metastases. Gastric recurrences occurred in 11 patients, and peritoneal and liver metastases occurred in 8 and 10 patients, respectively. Lymph node metastases were detected in 5 patients, but lymphovascular invasion was present in >50% of cases studied; these 2 were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 nongastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs; they usually occur in children and young adults, often have a chronic course similar to that of pediatric and CT GISTs, and have potential association with paraganglioma, necessitating long-term follow-up.
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PMID:Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. 2199 92

Gastrointestinal stromal tumors (GISTs) that lack kinase mutations often show loss of function of the succinate dehydrogenase (SDH) complex, due to germline mutation or promoter hypermethylation. SDH-deficient GISTs are exclusive to the stomach and have a multinodular architecture. It has been suggested that conventional risk stratification criteria may not predict outcome for this group of tumors, although data are limited. Here, we report the clinical, histologic, and genetic findings from a large cohort of 76 SDH-deficient GISTs diagnosed from 2005 to 2015, identified on the basis of histologic features or family history (45 female/31 male; mean age at diagnosis 32 y; range 11 to 71 y; 10 patients 50 y of age or above). Immunohistochemistry for SDHB and SDHA showed loss of SDHB in all cases and loss of SDHA in 28 (37%) tumors. Tumor size ranged from 1.9 to 22.5 cm; the primary tumor was multifocal in 29%. Mitotic rate ranged from 1 to 80 per 5 mm (median 5.5). Lymph node metastases were found at primary resection in 14 (18%) patients. Twenty-four patients (32%) had distant metastases at presentation, and 52 of 70 patients (74%) with follow-up developed distant metastases, most often to the liver, but also bone, lungs, breast, and brain. Applying conventional criteria (size and mitotic rate), 60% to 82% of patients with tumors ranging from very low risk to high risk for progressive disease developed distant metastases, regardless of the category. Carney-Stratakis syndrome and Carney triad were diagnosed in 6 and 8 patients, respectively. Of 35 patients tested, 26 harbored SDH mutations (11 SDHA, 8 SDHB, 6 SDHC, 1 SDHD). Follow-up data available for 70 patients ranged from 1 month to 39.3 years: 20 patients had no evidence of disease (mean 6.1 y), 32 were alive with metastases (mean 10.9 y), and 18 died of disease (mean 7.0 y after diagnosis). In summary, SDH-deficient GISTs account for approximately 8% of gastric GISTs and are associated with a high rate of distant metastasis, regardless of conventional risk category. Many affected patients have germline SDH mutations (most often SDHA). Identification of SDH-deficient GISTs is critical for prognostication and genetic counseling.
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PMID:Conventional Risk Stratification Fails to Predict Progression of Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumors: A Clinicopathologic Study of 76 Cases. 2734 Jul 50