Gain-of-Function Mutations of c- <i>kit</i> in Human Gastrointestinal Stromal Tumors

TLDR

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the digestive tract, with unknown molecular etiology and cellular origin, though they may arise from interstitial cells of Cajal that depend on SCF‑KIT signaling and express KIT and CD34. Sequencing of c‑kit from five GISTs uncovered activating mutations between the transmembrane and tyrosine‑kinase domains that constitutively activate KIT without ligand and transform Ba/F3 cells, implicating these mutations in GIST oncogenesis.

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c- kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c- kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.