Germline-Activating Mutation in the Kinase Domain of KIT Gene in Familial Gastrointestinal Stromal Tumors

Abstract

The proto-oncogene KIT encodes the receptor tyrosine kinase KIT. Gain-of-function mutations in the juxtamembrane domain of KIT have been reported in human gastrointestinal stromal tumors. In a family with multiple gastrointestinal stromal tumors and diffuse hyperplasia of myenteric plexus layer, we have identified another mutation of KIT, a single base mutation, resulting in the substitution of Glu for Lys(642) in the kinase I domain, and studied its biological effect in a cellular system. The mouse homologue of the human KIT mutant was generated by site-directed mutagenesis and stably transfected into the interleukin-3-dependent Ba/F3 murine cell line. The oncogenic potential of the mutated KIT was assessed in vitro by a proliferation assay and in vivo by transplantation into nude mice. Transfected Ba/F3 cells grew autonomously in absence of growth factors and formed tumors in nude mice. Substitution of Glu for Lys(642) is an oncogenic mutation in the tyrosine kinase domain of KIT. As germline heterozygous mutation, it causes a diffuse hyperplasia of myenteric interstitial cells of Cajal during embryonic development and occurrence of multiple gastrointestinal stromal tumors at adulthood.

Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

“…In contrast to sporadic gastrointestinal tumors that present with a single primary tumor, surgical intervention performed on an individual with a hereditary GIST may reveal tens to hundreds of tumor nodules. 3,5,7,[9][10][11][12][30][31][32] The mitotic rate of the tumors in most of these families (those who were documented) appear to be low suggesting that these tumors appear indolent compared with sporadic GIST. 3,9,10,12,13,30,33 Interestingly, 2 patients in our study presented with metastases at diagnosis despite displaying variable mitotic rates (1 with 5 mitoses per 50 hpf and 1 with 30 mitoses per 50 hpf.…”

“…We describe the clinical presentation, pattern of inheritance, histopathologic appearance of the tumors, clinical or radiographic efficacy of IM therapy and make molecular observations. The median age of diagnosis of all kindreds reported in the literature with GIST is 47 years of age, [3][4][5][6][7][8][9][10][11][12][13] notably earlier in onset than that of patients with the sporadic form of the disease where the median age of diagnosis is 60 years. 24,25 The age at diagnosis of GIST in one affected kindred appears to occur earlier in successive generations as noted by Robson et al 12 The mean age of diagnosis in the 4th generation was 34 years of age when compared with 62 years of age in the 2nd generation in that study.…”

“…In GIST kindreds, tumor nodules are often contiguous with areas of hyperplastic ICCs on histopathologic analysis 3,4,9,10,12,30,31,36 suggesting that these tumors arise within the hyperplastic ICC. In our study, the tumor nodules appeared to arise from a background of a hyperplastic Auerbach's plexus in the small bowel (Figs.…”

“…3 Most kindreds with familial GIST are stricken with a germ-line mutation in the KIT gene on chromosome 4 but there has been a report of a family with a PDGFRA gene mutation. [3][4][5][6][7][8][9][10][11][12][13] In families with GIST, the mutational site within KIT occurs most commonly in the juxtamembrane domain encoded by exon 11 (Table I). Since most of these kindreds are small and were described before the use of imatinib therapy, there are gaps in the knowledge of this entity.…”

Gastrointestinal stromal tumors: what do we know now?

“…26,27 These mice also develop GIST-like tumors. Diffuse ICC hyperplasia has been described in several kindreds with heritable mutations in KIT (Table 2), and is associated with dysphagia and the development of multiple GISTs, 26,29,53,[73][74][75][76][77][78] although many of the tumors do not follow a malignant course.…”