KIT activation is a ubiquitous feature of gastrointestinal stromal tumors.

TLDR

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the GI tract, are largely resistant to chemotherapy and radiation, and most express the KIT receptor tyrosine kinase, with a subset harboring activating KIT mutations. The study aimed to determine whether KIT expression and activation are universal features across benign, borderline, and malignant GISTs. Forty‑eight GISTs (10 benign, 10 borderline, 28 malignant) were examined by immunohistochemistry and mutation analysis to assess KIT expression and phosphorylation status. All tumors expressed KIT, 92 % harbored KIT mutations (71 % in the juxtamembrane region), mutations appeared in every histologic grade, and high‑level KIT activation was detected even in mutation‑negative cases, underscoring KIT activation as a ubiquitous therapeutic target.

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy. Most GISTs express the KIT receptor tyrosine kinase protein, and a subset of GISTs contain activating mutations within the KIT juxtamembrane region. We evaluated 48 GISTs, including 10 benign, 10 borderline, and 28 malignant cases, to determine whether KIT expression and activation are general properties of these tumors. Immunohistochemical KIT expression was demonstrated in each case. Somatic KIT mutations were found in 44 tumors (92%), of which 34 (71%) had juxtamembrane region mutations. Other GISTs had KIT mutations in the extracellular region (n = 6) and in two different regions in the tyrosine kinase domain (n = 4). Contrary to previous reports, KIT mutations were not identified preferentially in higher-grade tumors: indeed, they were found in each of 10 histologically benign GISTs. Notably, mutations in all KIT domains were associated with high-level KIT activation/phosphorylation, and KIT activation was also demonstrated in the four GISTs that lacked detectable KIT genomic and cDNA mutations. These studies underscore the role of KIT activation in GIST pathogenesis, and they suggest that activated KIT might represent a universal therapeutic target in GISTs.