Molecular characterization and pathogenesis of gastrointestinal stromal tumor

Abstract

Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. The sites of the tyrosine kinase gene mutations are associated with the biological behavior of GISTs, including risk category, clinical outcome and drug response. Mutations in RAS signaling pathway genes, including KRAS and BRAF, have also been reported in KIT/PDGFRA wild-type GISTs, though they are rare. Neurofibromin 1 (NF1) is a tumor suppressor gene mutated in neurofibromatosis type 1. Patients with NF1 mutations are at high risk of developing GISTs. Recent findings suggest that altered expression or mutation of members of succinate dehydrogenase (SDH) heterotetramer are causally associated with GIST development through induction of aberrant DNA methylation. At present, GISTs with no alterations in KIT, PDGFRA, RAS signaling genes or SDH family genes are referred to as true wild-type GISTs. KIT and PDGFRA mutations are thought as the earliest events in GIST development, and subsequent accumulation of chromosomal aberrations and other molecular alterations are required for malignant progression. In addition, recent studies have shown that epigenetic alterations and noncoding RNAs also play key roles in the pathogenesis of GISTs.

Keywords: DNA methylation; KIT; RAS; neurofibromin 1 (NF1); noncoding RNA; platelet-derived growth factor receptor alpha (PDGFRA); succinate dehydrogenase (SDH).

Figure 1

Key signaling pathways in GIST. The majority of GISTs harbor KIT or PDGFRA gain-of-function mutations, which lead to activation of downstream signaling, including via the MAPK, PI3K and STAT3 pathways. Minor populations of GISTs exhibit mutation of NF1, RAS or RAF, which leads to the activation of MAPK signaling. SDH deficiency also contributes to GIST development through activation of HIF1α and inhibition of DNA demethylation. GIST, gastrointestinal stromal tumor; NF1, neurofibromin 1; PDGFRA, platelet-derived growth factor receptor alpha.

Figure 2

KIT and PDGFRA mutations in GIST. (A) Locations and frequencies of KIT and PDGFRA mutations in sporadic GISTs; (B) locations of KIT and PDGFRA mutation in familial GISTs. GIST, gastrointestinal stromal tumor; PDGFRA, platelet-derived growth factor receptor alpha.

Figure 3

SDH-deficient GISTs caused by dysfunction of SDH complex. (A) SDH complex is a component of the citric acid cycle and respiratory electron transfer chain; (B) Carney Stratakis syndrome, Carney triad, and a subset of sporadic GISTs are included in SDH-deficient GISTs. SDH, succinate dehydrogenase; GIST, gastrointestinal stromal tumor.