Succinate dehydrogenase in KIT/PDGFRA wild-type gastrointestinal stromal tumors.

Abstract

10008 Background: 85% of GISTs in children are wildtype, lacking activating mutations in KIT or PDGFRA. The Carney-Stratakis Syndrome is an inherited predisposition to GIST and paraganglioma, caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C or D and resulting in dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic wildtype GIST. Methods: 38 patients with KIT- / PDGFRA- wildtype GIST without a family history of paraganglioma had testing for germline mutations in SDH. Thirteen pediatric KIT- / PDGFRA- wildtype GISTs lacking somatic mutations or deletions in SDH were evaluated for SDHB expression by immunohistochemistry (IHC), and western blotting. For comparison, SDHB expression was similarly evaluated in KIT-mutant GISTs and NF-1 associated GISTs. In addition, complex II activity was measured in a subset of the pediatric KIT- / PDGFRA-wildtype GISTs and in KIT-mutant GISTs. Results: 6 of 38 patients (16%) with KIT- / PDGFRA- wildtype GIST without a family history of paraganglioma had germline mutations in SDHB (n=3), C (n=1), or D (n=2). All pediatric KIT- / PDGFRA-wildtype GISTs lacking somatic mutations or deletions in SDH had complete loss of SDHB protein expression demonstrated by both IHC and western blotting while 75% of the KIT-mutant and 100% of the NF-1 associated GISTs had strong SDHB expression and none of these tumors demonstrated complete loss of SDHB expression. Complex II activity was absent (comparable to levels seen in SDH mutant paragangliomas) in pediatric KIT- / PDGFRA- wildtype GISTs lacking somatic SDH mutations or deletions. Conclusions: A germline mutation in SDHB, C or D can cause KIT- / PDGFRA- wildtype GIST without an associated family history of paraganglioma. In the absence of SDH mutations or deletions, pediatric KIT- / PDGFRA-wildtype GISTs have complete loss of SDHB protein expression and loss of complex II activity. These findings indicate that SDHB loss and defective cellular respiration may be central mediators of oncogenesis in GISTs lacking receptor tyrosine kinase mutations. No significant financial relationships to disclose.