Gastrointestinal stromal tumors 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% ... Gastrointestinal stromal tumors 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 can also be seen in neurofibromatosis-1 (NF1; 162200) due to mutations in the NF1 gene, and are thus distinct from the GISTs described here. Sandberg and Bridge (2002) reviewed the cytogenetics and molecular genetics of gastrointestinal stromal tumors. 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.
Lipton and Zuckerbrod (1966) described familial intestinal neurofibromatosis without other features of neurofibromatosis-1.
Verhest et al. (1981) described a Belgian family in which several individuals had 'intestinal neurofibromatosis.' In a follow-up of this family, Heimann et ... Lipton and Zuckerbrod (1966) described familial intestinal neurofibromatosis without other features of neurofibromatosis-1. Verhest et al. (1981) described a Belgian family in which several individuals had 'intestinal neurofibromatosis.' In a follow-up of this family, Heimann et al. (1988) reported that onset of symptoms was in adulthood and that some gene carriers remained asymptomatic into middle and late adulthood. A reciprocal balanced chromosomal translocation involving chromosomes 12 and 14 was identified, but did not segregate completely with the disorder and was thus considered to be a fortuitous finding (Verhest et al., 1988). Verhest et al. (1988) concluded that the disorder in this family was phenotypically distinct from NF1. De Raedt et al. (2006) provided further analysis of the Belgian family reported by Verhest et al. (1981) and Heimann et al. (1988). There were 5 affected members, including 3 living sisters who were examined. All had benign intestinal tumors, constipation, large hands, and coarse facies, and 2 had bowel obstruction necessitating several surgical interventions. Five tumors from 1 sister were available for pathologic investigation and showed a moderately cellular spindle cell proliferation with a typical wavy nature of a collagenous background. Although the histology was suggestive of neurofibromas, S100 protein expression was negative. Further studies showed negative staining for CD34 (142230), DOG1 (605882), and KIT. Genetic analysis revealed a germline mutation in the PDGFRA gene (173490.0010) in all 3 sisters. 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 systemic mast cell disease or urticaria pigmentosa, which is cutaneous mastocytosis. Isozaki et al. (2000) reported a French mother and son, 67 and 40 years old, respectively, 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) described an Italian family in which the mother had hyperpigmented spots and developed multiple GISTs with diffuse hyperplasia of the myenteric plexus, and her son had urticaria pigmentosa. Chompret et al. (2004) reported a French family in which 5 individuals developed multiple GISTs between 40 and 60 years of age. None had hyperpigmentation, mast cell disorders, or dysphagia, but all 5 had large hands, which was not present in unaffected family members. Pasini et al. (2007) reported a woman with GISTs and other mesenchymal tumors. She developed intestinal obstruction at age 32 years and was found to have multiple mesenchymal fibroid intestinal tumors. Tumor tissue showed multiple secondary genetic changes, including loss of heterozygosity of several chromosomal regions such as 14q. Of note, the patient had a history of a duodenal lipoma, which had not previously been reported in patients with GISTs. Genetic analysis identified a germline mutation in the PDGFRA gene (V561D; 173490.0004).
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 ... 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).
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 ... - Germline Mutations 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 woman with multiple GISTs and hyperpigmented spots, Beghini et al. (2001) identified a germline mutation in the KIT gene (V559A; 164920.0023). Her son, who had urticaria pigmentosa, also carried the mutation. In affected members of a French family with GISTs, Chompret et al. (2004) identified a heterozygous germline mutation in the PDGFRA gene (173490.0009). 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 (dbSNP 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.