Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene

Hirota, Seiichi; Nishida, Toshirou; Isozaki, Koji; Taniguchi, Masahiko; Nishikawa, Kazuhiro; Ohashi, Akiko; Takabayashi, Arimichi; Obayashi, T; Okuno, Tomoko; Kinoshita, Kazuo; Chen, Hui; Shinomura, Yasuhisa; Kitamura, Yukihiko

doi:10.1053/gast.2002.33024

Cited by 172 publications

(168 citation statements)

References 34 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…1-3) On the other hand, gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT have been reported in tumors arising from these cell lineages, such as mast cell tumors, 4,5) gastrointestinal stromal tumors (GISTs), [6][7][8][9][10][11][12][13] which are thought to originate from ICCs in the gastrointestinal tract, and germ cell tumors (GCTs).…”

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confidence: 99%

c‐kit gene mutations in intracranial germinomas

et al. 2004

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Gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT are found in most gastrointestinal stromal tumors and mastocytosis. Further, almost all gonadal seminomas/ dysgerminomas exhibit KIT membranous staining, and several reports have clarified that some (10-25%) have a c-kit gene mutation. But, whether intracranial germinomas also have a c-kit gene mutation remains unsolved. To elucidate the presence, frequency, and location of c-kit gene mutations in intracranial germinomas, we analyzed five mutational hot spots (exons 9, 10, 11, 13, and 17) in the c-kit genomic DNA of 16 germinomas using polymerase chain reaction and direct sequencing. We found c-kit gene mutations at exon 11 (W557C) or 17 (D816V, D820V, and N822Y) in four germinomas (25.0%), although no statistically significant difference in any clinicopathological factor was found between patients with or without mutations. These results are similar to those seen in gonadal seminoma/dysgerminoma patients, and confirm that intracranial germinomas are exact counterparts of gonadal seminomas/dysgerminomas, as would be expected on histological and immunohistochemical grounds. Moreover, molecular targeting drugs such as imatinib mesylate (STI571), which is a selective inhibitor of KIT, might be promising agents for the treatment of intracranial germinomas with c-kit gene mutations. he c-kit proto-oncogene encodes a receptor tyrosine kinase (KIT) that is a member of the same subfamily as the receptors for platelet-derived growth factor and colony-stimulating factor-1. KIT consists of an extracellular domain with five immunoglobulin-like repeats, a transmembrane domain, a juxtamembrane domain, and tyrosine kinase (TK) I and II domains split by a kinase insert. The ligand for KIT is stem cell factor (SCF). The SCF-KIT system is critical for the normal development and survival of melanocytes, erythrocytes, germ cells, mast cells, and interstitial cells of Cajal (ICCs).1-3) On the other hand, gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT have been reported in tumors arising from these cell lineages, such as mast cell tumors, 4,5) gastrointestinal stromal tumors (GISTs), [6][7][8][9][10][11][12][13] which are thought to originate from ICCs in the gastrointestinal tract, and germ cell tumors (GCTs).14-18) Four mutational hot spots in different regions of the c-kit gene have been identified: in exons 9, 11, 13, and 17. More recently, an additional activating c-kit gene mutation has been detected at exon 10 encoding the transmembrane domain. 19) Imatinib mesylate (STI571; Gleevec; Novartis Pharma, Basel, Switzerland) is a selective inhibitor of certain tyrosine kinases including KIT, and has proven very effective in the treatment of patients with advanced GISTs, which are resistant to conventional chemotherapy, especially those harboring c-kit mutations at exon 11. 20) However, mutant KIT with Asp816Val at exon 17, which is the most common type of c-kit mutation in adult mastocytosis, is resistant to ...

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Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene

Cited by 172 publications

References 34 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?

c‐kit gene mutations in intracranial germinomas

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