Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa

Abstract

BACKGROUND Gain‐of‐function mutations of the c‐kit protooncogene, mainly clustered in the juxtamembrane domain, have been reported in a significant fraction of gastrointestinal (GI) stromal tumors (GISTs) that represent the most common mesenchymal tumor of the GI tract. Two families also have been described with a GIST predisposition syndrome with a germline c‐kit mutation affecting either the juxtamembrane domain or the tyrosine kinase domain. Here, the authors report on a family in which the dominantly inherited trait of hyperpigmented spots was inherited from an individual who developed multiple GISTs with diffuse hyperplasia of the myenteric plexus by his son, who was affected with urticaria pigmentosa. METHODS Screening for the c‐kit mutation was performed by means of polymerase chain reaction‐based denaturing gradient gel electrophoresis/constant denaturing gel electrophoresis followed by direct sequencing of abnormal conformers. Expression of KIT and CD34 was determined by immunohistochemistry. RESULTS In peripheral blood DNA samples, both affected family members showed a previously undescribed c‐kit mutation in the juxtamembrane domain, resulting in the substitution of alanine for valine559. Mutation and polymorphic marker analyses on DNA samples from three GISTs and two skin biopsy specimens evidenced the same mutation in the heterozygous condition. Immunohistochemical examination showed coexpression of CD117 (c‐kit) and CD34 in all independent GISTs and CD117 positivity in mast cells from the skin lesions. CONCLUSIONS Comparative analysis of clinical presentation and mutation mapping in the families described to date point to the peculiar association of mast cells, melanocytic dysfunction, and GIST predisposition in carriers of c‐kit mutations within the juxtamembrane domain. Cancer 2001;92:657–62. © 2001 American Cancer Society.

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

“…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. As with the sporadic counterpart, the clinical behavior of GIST arising in the kindred can be aggressive even with low mitotic rates.…”

“…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.…”

“…Interestingly, GIST kindreds reported to date have been described to have primary GISTs arise from the small intestine 3,9,10,12,13,31,32,37,38 or the small intestine and the stomach 12,13,30,36,39 but not the stomach alone. On the other hand, studies have demonstrated that nearly two-thirds of all sporadic GISTs arise in the stomach.…”

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.…”

Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors

“…30 To our knowledge, B20 families with germline c-kit gene mutations and multiple GISTs have been reported so far. [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] Thirteen families including the first case have the c-kit gene mutation at exon 11, 30,31,33,34,[36][37][38][39][40]43,44,46,49 three families at exon 13, 32,45,48 three families at exon 17 35,42,47 and one family at exon 8. 41 In addition to multiple GISTs, patients of these families have hyperplasia of ICCs in the gut wall.…”