Classification of gastrointestinal stromal tumor syndromes
- Priya Gopie1,*,
- Lin Mei1,*,
- Anthony C Faber2,
- Steven R Grossman1,
- Steven C Smith3 and
- Sosipatros A Boikos1⇑
- 1Massey Cancer Center, VCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
- 2Phillips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
- 3Departments of Pathology and Surgery, VCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
- Correspondence should be addressed to S Boikos: sosipatros.boikos{at}vcuhealth.org
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Figure 1
Oncogenic molecular pathways in gastrointestinal stromal tumor (GIST). (A) The most common mutations in KIT-mutated GIST are exon 11 (juxtamembrane domain), exon 9 (extracellular domain), exon 13 (ATP-binding pocket) and exon 17 (activation loop). (B) The most common mutations in PDGFRA-mutated GIST are exon 18 (activation loop), exon 12 (juxtamembrane domain) and exon 14 (auto-inhibitory part of juxtamembrane domain). (C) Mutation of KIT or PI3K leads to constitutive activation of PI3K–AKT–mTOR pathway, resulting in enhanced growth signaling. (D) Mutation of PDGFRA, NF1, BRAF or RAS leads to mobilization of RAS–RAF–MEK–ERK pathway. Together with ETV1, these signals cause induced activation of proliferation. (E) Under normoxic conditions, hypoxia-inducible factor (HIF) 1a undergoes degradation by prolyl-hydroxylase domain (PHD) protein-mediated hydroxylation via ubiquitination. (F) Succinate dehydrogenase (SDH) is a mitochondrial enzyme (heterotetrameric, complex II). Subunits A/B are catalytic proteins localized on mitochondrial inner membrane, and subunits C/D are anchoring components. Inactivated mutation of these subunits causes accumulation of intracellular succinate, which competitively inhibits PHD proteins. Subsequent elevation of HIF-1a activity stimulates hypoxic signaling and associated tumorigenesis. (G) Succinate accumulation leads to inhibition of TET and KDM enzymes and global DNA and histone methylation changes, respectively.
- © 2018 Society for Endocrinology
