Familial gastrointestinal stromal tumor with hyperpigmentation: Association with a germline mutation of the c-kit gene

Maeyama, Hironobu; Hidaka, Eiko; Ota, Hiroyoshi; Minami, Satoshi; Kajiyama, Masashi; Kuraishi, Akira; Mori, Hiromitsu; Matsuda, Yoshiaki; Wada, Shinpei; Sodeyama, Harutsugu; Nakata, Satoshi; Kawamura, Nobuyuki; Hata, Satoru; Watanabe, Masahide; Iijima, Yoshihiro; Katsuyama, Tsutomu

doi:10.1053/gast.2001.20880

Cited by 206 publications

(126 citation statements)

References 16 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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%

mentioning

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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“…30,31,33,34,[36][37][38][39][40]43,44,46,49 KIT-Val559Ala mutation is the most frequent type, which has been detected in five families. 33,34,38,39,49 Recently, we found a germline mutation at exon 11, KIT-Tyr553Cys, in a 68-yearold woman with multiple GISTs. To our knowledge, this type of mutation has not been reported yet.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Nakai

Hashikura

Ohkouchi

et al. 2012

Laboratory Investigation

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We found a novel type germline mutation at exon 11 of the c-kit gene, which results in a substitution of Tyr to Cys at codon 553 of the c-kit gene product (KIT-Tyr553Cys), in a 68-year-old female patient with multiple gastrointestinal stromal tumors (GISTs). In the present study, we carried out mutational analysis in her family members to determine the carriers and characterized the mutation by introducing the corresponding mutation (murine KIT-Tyr552Cys) into expression vector possessing murine c-kit cDNA. Mutational analysis of peripheral blood leukocytes of her family members revealed that a 44-year-old son had the same mutation, but at present he had neither apparent symptoms nor images of multiple GISTs. By transfection with the expression vector possessing the murine mutant c-kit cDNA, interleukin-3-dependent Ba/F3 murine lymphoid cells started growing autonomously without any growth factors, indicating that the mutation was considered to be of gain-of-function. Imatinib, a small molecule of tyrosine kinase inhibitor, effectively inhibited autophosphorylation of KIT-Tyr552Cys. Nilotinib, another small molecule of the KIT inhibitor, also effectively inhibited autophosphorylation of KIT-Tyr552Cys. In fact, proliferation of Ba/F3 cells expressing KIT-Tyr552Cys was effectively inhibited by both imatinib and nilotinib. These findings indicate that the novel type human KIT-Tyr553Cys mutation is the cause of the present familial and multiple GISTs, and that both imatinib and nilotinib might effectively inhibit the growth of GISTs developing in the patients of this family.

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Familial gastrointestinal stromal tumor with hyperpigmentation: Association with a germline mutation of the c-kit gene

Cited by 206 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?

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

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