SNOMEDCT: 1187383001, 128755003, 420120006; ICD10CM: C49.A; ORPHA: 44890; DO: 9253;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.13 | Gastrointestinal stromal tumor | 606764 | Autosomal dominant; Isolated cases | 3 | SDHB | 185470 |
| 1q23.3 | Gastrointestinal stromal tumor | 606764 | Autosomal dominant; Isolated cases | 3 | SDHC | 602413 |
| 4q12 | Gastrointestinal stromal tumor, familial | 606764 | Autosomal dominant; Isolated cases | 3 | KIT | 164920 |
A number sign (#) is used with this entry because of evidence that gastrointestinal stromal tumor (GIST) can be caused by heterozygous germline mutation in the KIT gene (164920) on chromosome 4q12. GISTs are also seen in patients with somatic mutation in the KIT gene.
Rare cases of GIST have been reported with germline mutation in the SDHB gene (185470) on chromosome 1p36 and the SDHC gene (602413) on chromosome 1q23.
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al. (1999, 1999)).
GISTs are also seen as a feature in several syndromes, e.g., neurofibromatosis-1 (NF1; 162200) and GIST-plus syndrome (175510).
Nishida et al. (1998) reported a Japanese family in which 7 individuals spanning 4 generations had multiple GISTs. Inheritance was autosomal dominant. Most tumors were benign, but 1 patient had a malignant GIST. Two individuals reportedly had hyperpigmentation of the perineum. Nishida et al. (1998) noted that a woman reported by el-Omar et al. (1994) with multiple tumors that were probably GISTs also had hyperpigmentation of the perineal skin. In addition, Marshall et al. (1990) reported a family in which several members suffered from benign GISTs associated with either cutaneous or systemic mastocytosis (see 154800).
Isozaki et al. (2000) reported a French mother and son, aged 67 and 40 years, with multiple macroscopic GISTs, measuring from 1 to 8 cm, in duodenum and jejunum. All tumors examined were of low malignancy grade and neither patient had metastases.
Beghini et al. (2001) studied an Italian family in which 4 members over 3 generations, including a father and son, had multiple hyperpigmented spots. Both father and son had numerous dark-brown macules ranging in size from pinpoint dots to 5 mm and distributed on the skin of the face, trunk, extremities and mucous membranes. At 18 years of age, the father developed multiple GISTs with diffuse hyperplasia of the myenteric plexus; all tumors examined were benign or low malignancy-grade GISTs. The proband's 14-year-old son underwent evaluation of his skin lesions, and histology revealed groups of tightly packed round-to-ovoid mast cells around vessels of the upper and middle dermis; he was diagnosed with urticaria pigmentosa (see 154800).
Coffey et al. (2007) reviewed the clinical features, pathogenesis, and molecular treatments of Menetrier disease (137280) and GIST, both of which are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases.
Until about 1990, most gastrointestinal sarcomas were considered to be leiomyosarcomas because they resembled smooth muscle histologically. However, clinical oncologists observed a distinctly lower rate of response to standard doxorubicin-based regimens among leiomyosarcomas that arose in the gut than among those that arose in the uterus, trunk, or arms and legs. As early as 1983 immunocytochemical studies of gastrointestinal sarcomas documented their frequent absence of muscle markers that were typical of leiomyosarcomas located elsewhere in the body. Tumors in the subgroup without muscle or Schwann-cell (i.e., S100 antigen) markers were eventually termed gastrointestinal stromal tumors. Almost all of these tumors expressed KIT (164920) and often CD34, both of which are also expressed on hematopoietic progenitor cells (Miettinen et al. (1999, 1999)).
Chi et al. (2010) demonstrated that ETV1 (600541) is highly expressed in the subtypes of interstitial cells of Cajal (ICCs) sensitive to oncogenic KIT-mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth of imatinib-sensitive and -resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggested that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. Chi et al. (2010) proposed that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This model differs from other ETS-dependent tumors such as prostate cancer, melanoma, and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. Chi et al. (2010) also stated that this model of GIST pathogenesis represents a novel mechanism of oncogenic transcription factor activation.
Janeway et al. (2011) evaluated SDHB (185470) expression in 30 GISTs lacking KIT or PDGFRA (173490) mutations, 25 of which were also negative for associated SDH mutations confirmed by sequence analysis. Immunohistochemical studies showed lack of SDHB staining in 18 (100%) of 18 pediatric tumors, regardless of SDH mutation status, and in 8 (67%) of 12 adult tumors and weak expression in 4 (33%) of 12 adult tumors. By comparison, only 1 of 18 KIT-mutant GISTs and 0 of 5 NF1-associated GISTs lacked SDHB expression. These findings implicated a defect in respiration in the pathogenesis of some GIST tumors.
A subset of gastrointestinal stromal tumors (GISTs) lack canonical kinase mutations but instead have SDH deficiency and global DNA hypermethylation. Flavahan et al. (2019) associated this hypermethylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, Flavahan et al. (2019) mapped DNA methylation, CTCF (604167) insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant, and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, Flavahan et al. (2019) identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. Flavahan et al. (2019) focused on a disrupted insulator that normally partitions a core GIST superenhancer from the FGF4 (164980) oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. Flavahan et al. (2019) also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. The authors established a patient-derived xenograft from an SDH-deficient GIST that faithfully maintained the epigenetics of the parental tumor, including hypermethylation and insulator defects. This patient-derived xenograft model was highly sensitive to FGF receptor inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions.
Imatinib, formerly referred to as STI571, is an inhibitor of specific protein tyrosine kinases. It is highly effective in the treatment of both chronic myeloid leukemia (CML; 608232) and GISTs (Savage and Antman, 2002). Joensuu et al. (2001) described a Finnish patient with metastatic gastrointestinal stromal tumor who had a rapid and sustained complete response to treatment with imatinib daily for more than 12 months.
Balachandran et al. (2011) found that KIT val558del mice (Sommer et al., 2003) treated with imatinib had a rapid decrease in tumor weight and activity. This was associated with an increase in the number of activated CD8+ T cells and a decrease in the number of regulatory T cells within the tumor. Gene expression array indicated that these changes were mediated by reducing expression of the immunosuppressive enzyme IDO (147435) in tumor cells, whereas the expression of other immunomodulatory cytokines was not changed. In human GIST cells, imatinib inhibited KIT activation and IDO expression; IDO expression was also found to be regulated by mTOR (601231) and ETV4 (600711). In human GIST specimens, the CD8+ T cell profile correlated with sensitivity to imatinib and decreased IDO expression. Finally, in mice, concurrent immunotherapy using CTLA4 (123890) blockade augmented the efficacy of imatinib in GIST. The findings indicated that T cells are crucial to the antitumor effects of imatinib in GIST, and suggested that concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.
Germline Mutations in KIT
In affected members of a Japanese family with multiple GISTs, Nishida et al. (1998) identified a germline deletion in the KIT gene (164920.0017).
In a French mother and son with multiple GISTs, Isozaki et al. (2000) identified a gain-of-function germline mutation in the KIT gene (K642E; 164920.0024).
In an Italian man with multiple GISTs and hyperpigmented spots, Beghini et al. (2001) identified a germline mutation in the KIT gene (V559A; 164920.0023). His 14-year-old son, in whom the hyperpigmented lesions had been shown to represent cutaneous mastocytosis (MASTC; 154800) also carried the mutation.
Germline Mutations in SDH Subunit Genes
Janeway et al. (2011) identified 3 germline mutations in the SDHB gene (see, e.g., 185470.0004) in 3 different patients with sporadic occurrence of GIST. The patients were 18, 22, and 21 years old, and none had a personal or family history of paragangliomas. Tumor tissue available from 2 of these patients showed lack of SDHB immunostaining. A fourth patient, who was 16 years old, carried a germline mutation in the SDHC gene (602413.0004). Overall, mutations in SDH subunit genes accounted for 4 (12%) of 34 patients with isolated GIST lacking KIT or PDGFRA mutations.
Somatic Mutations
Hirota et al. (1998) identified somatic gain-of-function mutations in the KIT gene (see, e.g., 164920.0011-164920.0015) in 5 of 6 GISTs. Most GISTs were solitary and the mutations resulted in constitutive activation of the KIT gene. Miettinen et al. (1999) stated that gastrointestinal stromal tumors with mutant KIT were more likely to be high-grade tumors, characterized by more frequent recurrences and a higher mortality rate compared to gastrointestinal stromal tumors with normal KIT.
Heinrich et al. (2003) found that approximately 35% (14 of 40) of GISTs lacking KIT mutations had somatic intragenic activation mutations in the PDGFRA gene (see, e.g., 173490.0001-173490.0007). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Heinrich et al. (2003) concluded that KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
Modifier Genes
Delahaye et al. (2011) found an association between alternatively spliced exon 4 isoforms of the NCR3 gene (611550) and prognosis in GIST. In a study of 44 GIST tumors, tumor-infiltrating NK cells showed downregulation of NCR3 compared to circulating cells of healthy volunteers. The density of the NK cell infiltrate was inversely correlated with the presence of metastasis at diagnosis, suggesting an NK cell-mediated immunosurveillance mechanism in these tumors. RT-PCR studies of peripheral blood from 80 patients with GIST showed preferential expression of the immunosuppressive NCR3c isoform in 53%, compared to healthy volunteers, of whom only 30% expressed isoform NCR3c (p = 0.02). NK cells from GIST patients with the NCR3c isoform showed a defect in NCR3-driven NK effector functions. A retrospective analysis of 80 GIST patients treated with imatinib showed decreased overall survival in those with the NRC3c isoform compared to those with NRC3a and NRC3b isoforms (p = 0.001). Delahaye et al. (2011) also found an association between a 3790T-C SNP (rs986475) in the promoter region of the NCR3 gene, as well as other SNPs, and expression of the NCR3c isoform. The findings suggested that the genetically determined NCR3 status may predict clinical outcome in patients with GIST.
Reviews
Sandberg and Bridge (2002) reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors.
Patients with familial GISTs usually have multiple tumors; those with germline mutations in the KIT gene may also have hyperpigmentation, mast cell tumors, or dysphagia, whereas those with mutations in the PDGFRA gene often have large hands (Chompret et al., 2004).
The form of familial GIST previously referred to as 'intestinal neurofibromatosis' and symbolized NF3B (or NF3) should not be confused with neurofibromatosis type III of Riccardi (162260), designated NF3A (or NF3).
In a review, Coffey et al. (2007) stated that gain-of-function mutations in Kit lead to GIST in mice.
Sommer et al. (2003) generated a mouse model of GIST by knockin of a Kit exon 11-activating mutation, val558del, which corresponds to a val559del mutation (164920.0017) found in human familial GISTs. Heterozygous male and female mice were fertile, but fertility was impaired with increasing age. Heterozygous mice developed symptoms of disease and eventually died from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells was evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. Sommer et al. (2003) concluded that mice heterozygous for a val558 deletion in the Kit gene reproduce human familial GISTs and may be used as a model for studying the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrated that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal.
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