Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations

• Published in: Human pathology 2002-05, Vol.33 (5), p.484-495
• Main Authors: Heinrich, Michael C., Rubin, Brian P., Longley, B.Jack, Fletcher, Jonathan A.
• Format: Article
• Language: English
• Subjects: Chromosome Aberrations; cytogenetics; Female; gastrointestinal neoplasm; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - metabolism; Gastrointestinal Neoplasms - pathology; Gene Expression Regulation, Neoplastic; Humans; Karyotyping; Male; mutation; oncogenic; Proto-Oncogene Proteins c-kit - biosynthesis; Proto-Oncogene Proteins c-kit - genetics; receptor tyrosine kinase; sarcoma; Sarcoma - genetics; Sarcoma - metabolism; Sarcoma - pathology; Signal Transduction; Stromal Cells - metabolism; Stromal Cells - pathology
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1053/hupa.2002.124124

Recent studies have done much to reveal the biological and genetic underpinnings of gastrointestinal stromal tumors (GISTs). Constitutive activation of the KIT receptor tyrosine kinase is a central pathogenetic event in most GISTs and generally results from oncogenic point mutations which can involve either extracellular or cytoplasmic domains of the receptor. Oncogenic mutations enable the KIT receptor to phosphorylate various substrate proteins, leading to activation of signal transduction cascades which regulate cell proliferation, apoptosis, chemotaxis, and adhesion. KIT mutations can be broadly assigned to 2 groups, those that involve the “regulatory” regions responsible for modulating KIT enzymatic activity and those that involve the enzymatic region itself. In vitro studies suggest that GISTs with regulatory-region KIT mutations are more likely to respond to STI-571 than are GISTs with enzymatic-region mutations. A minority of GISTs lack demonstrable KIT mutations, but KIT is nonetheless strongly activated. Such GISTs might contain KIT mutations which are not readily detected by conventional screening methods, or alternately, KIT might be activated by nonmutational mechanisms. Most GISTs have noncomplex cytogenetic profiles, often featuring deletions of chromosomes 14 and 22. Additional chromosomal aberrations are acquired as the GISTs progress to higher histologic grade. These cytogenetic aberrations are undoubtedly important in GIST pathogenesis, but currently they do not play a key role as diagnostic adjuncts. HUM PATHOL 33:484-495. Copyright 2002, Elsevier Science (USA). All rights reserved.