Diagnostic criteria, specific mutations, and genetic predisposition in gastrointestinal stromal tumors

Abstract

In 1998, gastrointestinal stromal tumor (GIST) emerged as a distinct oncogenetic entity and subsequently became a paradigm of targeted therapies in solid tumors. Diagnosis of GIST relies on both histology and immunohistochemistry. Ninety-five percent of GISTs express either KIT or DOG-1. Approximately 80%–90% of GISTs harbor gain-of-function mutations of either KIT or platelet-derived growth factor receptor alpha polypeptide (PDGFRA) receptor tyrosine kinase (RTK). More than 100 different mutations have been described, some of which are associated with specific clinical and/or histological characteristics. Detection of KIT or PDGFRA mutations is recommended in advanced GISTs because they are highly predictive of tumor response to RTK inhibitors, as well as in KIT-negative cases to confirm diagnosis. In most cases, GISTs are sporadic, but in rare cases, they are related with genetic predisposition, such as neurofibromatosis type 1, Carney triad, Carney–Stratakis syndrome, and inherited KIT or PDGFRA germline mutations.

Gene Expression Patterns of Hemizygous and Heterozygous KIT Mutations Suggest Distinct Oncogenic Pathways: A Study in NIH3T3 Cell Lines and GIST Samples

“…In these tumors, Wnt activation resulted in cell proliferation via upregulation of the TCF/β-catenin target gene CDC25A which plays a nonredondant role in regulating cell cycle [51]. Nf1 which is a negative regulator of the ras signal transduction pathway, mutated in neurofibromatosis type 1, also confers an increased risk of developing WT GISTs [52]. Ulk1, which plays an essential role in autophagosome formation through activation or regulation of the AMP activated protein kinase and mTOR, is overexpressed in esophagus squamous cell carcinoma [53].…”

Esophageal Gastrointestinal Stromal Tumors Presenting as Mediastinal Mass

“…Initially, ‘GIST’ applied to neoplasms displaying only c-kit (CD117), but the diagnosis is based on histopathology and immunohistochemistry [ 6 ]. A total of 95% of GISTs express KIT or DOG 1 and have mutations in KIT or platelet-derived growth factor receptor, α polypeptide [ 7 ]. The KIT-positive cells in abdominal soft tissues include mast cells in the wall of the gastrointestinal tract; the interstitial cells of Cajal (intestinal pacemakers) around the myenteric plexus were thought to be the origin of GISTs.…”