Familial gastrointestinal stromal tumours with germline mutation of the KIT gene

Nishida, Toshirou; Hirota, Seiichi; Taniguchi, Masahiko; Hashimoto, Koji; Isozaki, Koji; Nakamura, Harumi; Kanakura, Yuzuru; Tanaka, Tomoyuki; Takabayashi, Arimichi; Matsuda, Hikaru; Kitamura, Yukihiko

doi:10.1038/1209

Cited by 541 publications

(353 citation statements)

References 16 publications

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“…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.…”

Section: Discussionmentioning

confidence: 95%

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

Kleinbaum

Lazar

Tamborini

et al. 2007

Intl Journal of Cancer

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Germ-line mutations in the KIT receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). There is limited information from large kindreds regarding median age at diagnosis, detailed histopathology, clinical effects of imatinib therapy and chromosomal abnormalities of the KIT gene. We identified a large kindred with GIST. Each family member was interviewed and appropriate medical records and radiographic imaging were obtained. Archival tumor tissue was obtained to confirm diagnosis, extract genomic DNA and perform fluorescent in situ hybridization cytogenetics of the KIT gene. Fifteen of 79 individuals with GIST were identified in this kindred. There were 8 males, the mean age at diagnosis was 53.9 (range 45-71) years. Histopathology revealed microscopic proliferation and nodularity in the myenteric plexus, spindled morphology, diffuse Kit but variable CD34 staining and low mitotic rates in the setting of metastatic disease. A deletion of codon 579 in exon 11 of the KIT gene was identified in tumor and normal tissue of this family. Mutation and cytogenetic analysis revealed homozygous loss of the wild-type KIT sequence in tumor from one individual. Four of 4 individuals treated with imatinib are alive and without progression while 9 of 11 individuals not treated with imatinib are deceased. This study describes a kindred with a propensity to develop GIST in an autosomal dominant pattern. Germ-line deletion of KIT codon 579 in GIST is associated with clinical benefit from imatinib, limited utility of mitoses to predict malignant potential, and a novel homozygous deletion of this codon in one individual. ' 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 95%

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

Kleinbaum

Lazar

Tamborini

et al. 2007

Intl Journal of Cancer

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“…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.…”

Section: Interstitial Cells Of Cajalmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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“…mains in exon 11 of c-kit have been shown in GISTs 7,19 and in a mast cell leukemia cell line. 20 The c-kit mutations in GISTs have been shown to lead to ligand-independent activation of the tyrosine kinase of c-kit and have a tumor promoting effect in vitro.…”

mentioning

confidence: 99%

Mutations in Exon 11 of c-Kit Occur Preferentially in Malignant versus Benign Gastrointestinal Stromal Tumors and Do Not Occur in Leiomyomas or Leiomyosarcomas

Lasota

Jasiński

Sarlomo-Rikala

et al. 1999

The American Journal of Pathology

503

320

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Gastrointestinal stromal tumors (GISTsGastrointestinal stromal tumor (GIST) is the designation for a major subset of mesenchymal tumors of the gastrointestinal tract. These tumors differ from ordinary leiomyomas and leiomyosarcomas histologically, immunohistochemically and genetically. GISTs are typically more cellular than ordinary leiomyomas and are composed of spindle or epithelioid-appearing cells. Immunohistochemically they are typically positive for CD34, the hematopoietic progenitor cell antigen, but negative for desmin, in contrast to leiomyomas and leiomyosarcomas.

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Familial gastrointestinal stromal tumours with germline mutation of the KIT gene

Cited by 541 publications

References 16 publications

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

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

Gastrointestinal stromal tumors: what do we know now?

Mutations in Exon 11 of c-Kit Occur Preferentially in Malignant versus Benign Gastrointestinal Stromal Tumors and Do Not Occur in Leiomyomas or Leiomyosarcomas

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