c‐kit Gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors

Kinoshita, Kazuo; Isozaki, Koji; Hirota, Seiichi; Nishida, Toshirou; Chen, Hui; Nakahara, Masanori; Nagasawa, Yutaka; Ohashi, Akiko; Shinomura, Yasuhisa; Kitamura, Yukihiko; Matsuzawa, Yūji

doi:10.1046/j.1440-1746.2003.02911.x

Cited by 78 publications

(70 citation statements)

References 27 publications

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“…On the other hand, autophosphorylation of KIT-Dup-Ala502Tyr503 was observed without SCF stimulation as reported ( Figure 3). 16 Similarly, autophosphorylation of KIT-Dup-Ser501Ala502 was detected even without SCF stimulation, demonstrating that the mutation is also of gain-of-function ( Figure 3). …”

Section: Constitutive Activation Of Kit-dup-ser501ala502mentioning

confidence: 87%

mentioning

confidence: 99%

“…1,11,12 The majority of the c-kit gene mutations (B90%) are present at exon 11 encoding the juxtamembrane domain, 1,13,14 fewer (B10%) at exon 9 encoding the extracellular domain, [13][14][15] and rare (B1%) at exon 13 encoding the TKD I 14,16 or at exon 17 encoding the TKD II. 14,16 Various types of the mutations have been reported at exon 11, while most exon 9 mutations are a particular internal tandem duplication of Ala502Tyr503 (KIT-Dup-Ala502Tyr503). [13][14][15] Only a few GIST cases have been reported to possess duplication of Phe506Ala507Phe508, 17,18 deletion of Lys484His485Asn486Gly487, 18 complex deletion/ insertion of 14 amino acid (490-503) to AspHisIle ValValSerLeuThr 19 and substitution of Pro456Ser.…”

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confidence: 99%

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Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503

Liu

Ohkouchi

Hashikura

et al. 2013

Laboratory Investigation

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The great majority of gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of the c-kit gene, which encodes KIT receptor tyrosine kinase. Most of the mutations are located at exon 11, but some are at exon 9 or at other exons. Mutation types at exon 11 vary, while most mutations at exon 9 are a particular duplication of Ala502Tyr503 (KIT-Dup-Ala502Tyr503). Recently a duplication of Ser501Ala502 (KIT-Dup-Ser501Ala502) at exon 9 has been reported in two cases of pediatric mastocytosis and one case of adult mast cell leukemia. Although KIT-Dup-Ser501Ala502 had not been reported in GISTs, we found two GIST cases possessing the mutation in 45 GIST cases with exon 9 c-kit gene mutations, among a total of approximately 500 GIST cases examined. In this report, we briefly summarize clinicopathological findings of the two cases, and characterize the biology of the mutation. When autophosphorylation of KIT-Dup-Ser501Ala502 was examined by transient transfection of c-kit cDNA with Dup-Ser501Ala502 into CHO-K1 cells, KIT-Dup-Ser501Ala502 was ligand-independently activating. The inhibitory effect of selective tyrosine kinase inhibitors, imatinib and nilotinib, on KIT-Dup-Ser501Ala502 was examined and compared with that of KIT-Dup-Ala502Tyr503. Imatinib efficiently inhibited constitutive activation of KIT-Dup-Ser501Ala502 at a concentration of 0.1 mM, whereas it inhibited that of KIT-Dup-Ala502Tyr503 at a concentration of 10 mM. Constitutive activation of KIT-Dup-Ser502Ala503 was not inhibited by nilotinib even at a concentration of 10 mM but that of KIT-Dup-Ala501Tyr502 was almost completely inhibited at a concentration of 1 mM. The results suggest that imatinib and nilotinib could be more effective on GISTs with KIT-Dup-Ser501Ala502 than those with KIT-Dup-Ala502Tyr503. In fact, a patient with KIT-Dup-Ser501Ala502 showed longterm stable disease with administration of the usual dose of 400 mg imatinib. Although mutation sites of KIT-DupSer501Ala502 and KIT-Dup-Ala502Tyr503 are closely located, imatinib-and nilotinib-sensitive KIT-Dup-Ser501Ala502 are distinguishable from KIT-Dup-Ala502Tyr503.

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Section: Constitutive Activation Of Kit-dup-ser501ala502mentioning

confidence: 87%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503

Liu

Ohkouchi

Hashikura

et al. 2013

Laboratory Investigation

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“…1,[15][16][17][18][19][20][21][22][23] Similarly, germline loss-of-function mutations of the c-kit gene in various W mutant mice are often observed at exon 11, exon 13 or exon 17. 52 Mutation of murine c-kit gene at codon 582, KIT-Gln582Lys, corresponding to human KITGln583Lys is a cause of W 37 loss-of-function mutant mice.…”

Section: Discussionmentioning

confidence: 99%

“…15,21,23 In melanomas, most of the mutations are also present at exon 11. 19,20 However, most of them are located at exon 17 in both human mast cell tumors and germ cell tumors.…”

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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A recurrent duodenal gastrointestinal stromal tumor with a frameshift mutation resulting in a stop codon in KIT exon 13

Vũ¹,

Xinh²,

Kikushima³

et al. 2004

Genes Chromosomes & Cancer

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Gastrointestinal stromal tumors (GISTs) are a specific and rare subset of human gastrointestinal tract tumors. Most GISTs show gain-of-function mutations of KIT, mainly in exon 11, that always maintain the reading frame. We report on data from a 43-year-old Japanese man with recurrent duodenal GIST and a frameshift mutation in KIT exon 13 together with an in-frame deletion in KIT exon 11 detected by genomic DNA sequencing. Deletion of 48 base pairs of KIT exon 11, which preserved the reading frame, was identified in both primary and recurrent tumors, whereas deletion of one nucleotide of codon 642 of KIT exon 13, which changed the reading frame and induced a novel stop codon at amino acid 644, was found only in the recurrent tumor. The predicted protein resulting from the latter would lack part of the kinase domain. To the best of our knowledge, this is the first documentation of a GIST with a frameshift mutation of KIT.

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c‐kit Gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors

Abstract: The mutation at exons 17 or 13 was considered to be very rare in sporadic GIST.

Cited by 78 publications

References 27 publications

Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503

Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503

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

A recurrent duodenal gastrointestinal stromal tumor with a frameshift mutation resulting in a stop codon in KIT exon 13

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