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

doi:10.1053/hupa.2002.124124

Human Pathology

Volume 33, Issue 5, May 2002, Pages 484-495

https://doi.org/10.1053/hupa.2002.124124 Get rights and content

Abstract

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.

Section snippets

KIT activation: A central tumorigenic event in GISTs

Many GISTs express constitutively activated KIT oncoproteins. The oncogenic activation of these KIT proteins does not depend on binding of KIT ligand; rather, KIT oncoproteins in GISTs often have structural changes which favor receptor oligomerization and cross-phosphorylation, even in the absence of ligand binding (Fig 3).13, 14, 15

. Oncogenic mutations of the KIT juxtamembrane domain result in ligand-independent KIT dimerization and activation of the kinase enzymatic domain. KIT activation is

Mechanisms of KIT regulation and dysregulation

As is the case with most RTKs, KIT kinase activity has multiple levels of control. Disruption of any of several control mechanisms may lead to aberrant kinase activation and oncogenesis. KIT kinase activity is controlled first and foremost by developmentally specific expression of the KIT protein. (If there is no protein expression, then there is no kinase activity). In the absence of ligand, normal KIT exists as a monomer in which enzymatic activity is inhibited by intrinsic structural

Biological consequences of KIT activation in GISTs

KIT activation normally occurs when the receptor is bound by its cognate ligand, stem-cell factor. Ligand-mediated KIT activation triggers various cell-signaling cascades that regulate cell behavior.45, 46 Examples of critical downstream signaling mechanisms include activation of cell survival (antiapoptotic) proteins, such as AKT, and cell proliferation–related proteins, such as MAPK p42/p44.45, 46 An intriguing aspect of KIT oncoproteins in hematologic neoplasms is that the exact signaling

Alternate KIT activation mechanisms in GISTs

KIT signaling pathways are activated in virtually all GISTs, and most GISTs have oncogenic mutations within the coding sequence of the KIT gene. However, even those tumors that lack such mutations can have biochemical features of high-level KIT kinase activation.¹⁵ As discussed later, KIT might be activated oncogenically by several alternate, nonmutational mechanisms, but to our knowledge, none of these mechanisms has been tested rigorously. It is important to consider alternative (i.e.,

Cytogenetic mechanisms in the progression from low-grade to high-grade GIST

Most GISTs have 1 or more chromosomal deletions, and the cytogenetic profile in GISTs is quite different from that in histologic mimics such as leiomyoma and leiomyosarcoma (Table 1).

. Characteristic cytogenetic and molecular events in GISTs and in mesenchymal tumors that can masquerade as GISTs

Tumor Type	Characteristic Cytogenetic Events	Molecular Events
Gastrointestinal stromal tumor	Monosomies 14 and 22
	Deletion of 1p
		KIT mutation
Desmoid	Deletion of 5q	APC mutation
	Trisomies 8 and 20
Endometrial stromal

Summary

This review has outlined the considerable recent progress in our understanding of biological and genetic mechanisms in GISTs. Our intention has been to emphasize aspects of GIST “basic science” that are germane to the intriguing clinicopathologic features of GISTs. Our focus has been primarily on science and biological mechanisms rather than on clinical correlates. The relevance and application of these scientific advances, in the pathology and clinical fields, is discussed in several companion

Acknowledgements

The authors thank Nora Joseph and Dr. Anette Duensing, who provided figures for this review.

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Due to the increasing recognition of gastrointestinal stromal tumor (GIST), novel insights have appeared in both preclinical and clinical research and begun to reshape the field. This study aims to map the research landscape through bibliometric analysis and provide a brief overview for the future of the GIST field.
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Genomic alterations of KIT are commonly found in gastrointestinal stroma tumors, seminoma, and acute myeloid leukemia.30–32 Activating missense mutations in the kinase domain are the most common somatic alteration in cancer, but recurrent splice site changes have also been described.33,34 Although the significance of this mutation in this case is unclear, its enrichment in gastrointestinal stroma tumors, which are known to be driven by genomic alterations in KIT, suggests a potential driver function.
Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.
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The KIT is a receptor protein encoded by the c-kit proto-oncogene present on chromosome 4 [8,9]. The stem cell factor (SCF) is responsible for its activation under normal circumstances, acting as the initiator of the downstream signaling cascades [3,6,10,11]. The architecture of the KIT receptor is similar to the other members of the type III RTK family, which consists of an SCF binding extracellular domain (ECD), an intracellular domain (ICD), and a transmembrane domain (TMD) [11-13].
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^*: Address correspondence and reprint requests to Jonathan A. Fletcher, MD, Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

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GIST SymposiumBiology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations*

Abstract

Section snippets

KIT activation: A central tumorigenic event in GISTs

Mechanisms of KIT regulation and dysregulation

Biological consequences of KIT activation in GISTs

Alternate KIT activation mechanisms in GISTs

Cytogenetic mechanisms in the progression from low-grade to high-grade GIST

Summary

Acknowledgements

Trends Genet

Adv Genet

Blood

Gastroenterology

Gastroenterology

Gastroenterology

Am J Pathol

Gastroenterology

Blood

Blood

Am J Pathol

Am J Pathol

Am J Pathol

J Biol Chem

Leuk Res

Blood

J Invest Dermatol

Cell

J Invest Dermatol

Am J Pathol

Int J Biochem Cell Biol

Hematol Oncol Clin North Am

Blood

Biochem Biophys Res Commun

Blood

J Biol Chem

Blood

Int J Biochem Cell Biol

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

c-kit protein, a transmembrane kinase: Identification in tissues and characterization

Mol Cell Biol

Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis

EMBO J

Structure-function analyses of the KIT receptor for the Steel factor

Stem Cells

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