Succinate dehydrogenase deficiency in a PDGFRA mutated gastrointestinal stromal tumor.

Most gastrointestinal stromal tumors harbor mutually exclusive gain-of-function mutations in the receptor tyrosine kinase (RTK) KIT (70-80%) or in the related receptor PDGFRA (~10%). Mutations in PDGFRA are most commonly found in the TK domain encoded by exon 18, conferring resistance to approved tyrosine kinase inhibitors (TKI). A more recently defined subset of GIST exhibit deficiencies in the succinate dehydrogenase (SDH) enzyme complex as a result of genetic or epigenetic inactivation of one of the four SDH subunit genes (SDHA-D). SDH-deficient GISTs generally lack mutations in KIT and PDGFRA and do not respond to imatinib (IM), although these GISTs may respond to TKIs targeting VEGFR, such as sunitinib and regorafenib. Whole-exome sequencing (WES) of two GISTs from a single case carrying the IM-resistant exon 18 PDGFRA mutation D842V was carried out to identify additional potential targets for therapy. Surprisingly, a somatic mutation in exon 4 of the SDHB subunit gene (c.291_292delCT, p.I97Mfs*21) was identified in both tumors. Sanger sequencing confirmed the presence of this inactivating mutation, and immunohistochemistry for the SDHB subunit demonstrated that these tumors were in fact SDH deficient. IHC for the SDHB subunit across a panel of ~100 GIST cases failed to detect SDH deficiency in other GISTs with RTK mutations. To our knowledge this is the first reported case of an SDH-deficient GIST harboring a gain-of-function mutation in the PDGFRA receptor, and this finding has implications for the molecular-based classification and treatment of GIST. Citation Format: Martin G. Belinsky, Lori Rink, Kathy K. Cai, Biao Luo, Yan Zhou, Margaret von Mehren. Succinate dehydrogenase deficiency in a PDGFRA mutated gastrointestinal stromal tumor [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A02.