Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.

Keywords: gastrointestinal stromal tumor; insulin-like growth factor receptor; review; succinate dehydrogenase; wild type.

Figure 1

Immunohistochemical analysis of KIT, IGF1R, SDHB, and SDHA expression in WT and KIT mutant GISTs. Primary antibodies used include KIT (Dako), IGF1R (Cell Signaling), SDHB (Abcam), and SDHA (Abcam). Positive KIT staining is evident throughout tumor tissue in all cases (A,E,I,M). Strong staining for IGF1R is seen in the WT GISTs (B,F,J) but not in the KIT mutant GIST (N). SDHB staining is evident in the mutant GIST (O) and in the adjacent normal tissue and epithelial cells in the WT cases, but absent in the tumor tissue (C,G,K). SDHA staining is absent in an SDHB-deficient GIST with a truncating SDHA mutation (D). Positive SDHA staining is evident in an SDHB-deficient GIST harboring compound heterozygous missense SDHA mutations (H), and in an SDHB-deficient GIST with no identified SDH mutations (L) as well as in the mutant GIST (P). See text for more detailed mutation descriptions. GIST cases have been previously reported (Belinsky et al., 2012): (A–D), case 2; (E–H), case 1; (I–L), case 10; (M–P), case 21.

Figure 2

Distribution of reported SDHA gene mutations in GIST. Boxed numbers indicate exons, connecting lines represent introns (not drawn to scale), U = 5′, 3′ untranslated regions. Mutations are annotated at the cDNA and protein level, followed by the number of reported cases in parentheses. *Indicates stop codon. ^#Mutations reported in paraganglioma.

Figure 3

Induction of the pseudohypoxic response in SDH-deficient GIST. SDH, composed of the catalytic subunit (SDHA and SDHB) anchored to the inner mitochondrial membrane through subunits SDHC and SDHD, oxidizes succinate to fumarate as part of the tricarboxylic acid (TCA) cycle and couples this oxidation to the reduction of Coenzyme Q (CoQ, ubiquinone) as complex II of the electron transport chain (not shown). Inactivation of SDH via SDHX gene mutation or other mechanisms leads to succinate accumulation in the mitochondria and subsequent export to the cytosol via metabolite transporters (not shown). Increased cytosolic succinate levels act to stabilize one of three HIFα subunits (HIF1α is shown for simplicity) via product inhibition of PHD-mediated hydroxylation of HIF1α, which skirts the VHL-mediated targeting of HIF1α for degradation. Stabilization and nuclear translocation of HIF1α leads to formation of the heterodimeric HIF transcription factor with constitutively expressed nuclear-located HIF1β, and induction of the pseudohypoxic response.