Multiple gastrointestinal stromal tumors with a germline <i>c‐kit</i> mutation

Kim, Hyun Jung; Lim, Sung‐Jig; Park, Kyeongmee; Yuh, Young Jin; Jang, Se Jin; Choi, Jeongyong

doi:10.1111/j.1440-1827.2005.01885.x

Cited by 46 publications

(24 citation statements)

References 19 publications

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“…The normal cells of patients with familial GIST exhibit a germ-line heterozygous KIT mutation. However, the large and more aggressive GISTs of familial GIST patients often harbor a homozygous KIT mutation, 36,37 further supporting our findings. Although these three patients bear large tumor burden, of note, homozygous KIT mutation has been reported in small minimal GISTs.…”

Section: Discussionsupporting

confidence: 79%

Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression

et al. 2008

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Activating mutation in KIT or platelet-derived growth factor-a can lead to gastrointestinal stromal tumors (GISTs). Eighty-four cases from two institutes were analyzed. Of them, 62 (74%) harbored KIT mutations, 7 of which are previously unreported. One exhibited duplication from both intron 11 and exon 11, which has not been reported in KIT in human cancer. A homozygous/hemizygous KIT-activating mutation was found in 9 of the 62 cases (15%). We identified three GIST patients with heterozygous KIT-activating mutations at initial presentation, who later recurred with highly aggressive clinical courses. Molecular analysis at recurrence showed total dominance of homozygous (diploid) KIT-activating mutation within a short period of 6-13 months, suggesting an important role of oncogene homozygosity in tumor progression. Topoisomerase II is active in the S-and G 2 phases of cell cycle and is a direct and accurate proliferative indicator. Cellular and molecular analysis of serial tumor specimens obtained from consecutive surgeries or biopsy within the same patient revealed that these clones that acquired the homozygous KIT mutation exhibited an increased mitotic count and a striking fourfold increase in topoisomerase II proliferative index (percentage cells show positive topoisomerase II nuclear staining compared to the heterozygous counterpart within the same patient. KIT forms a homodimer as the initial step in signal transduction and this may account for the quadruple increase in proliferation. Using SNPs for allelotyping on the serial tumor specimens, we demonstrate that the mechanism of the second hit resulting in homozygous KIT-activating mutation and loss of heterozygosity is achieved by mitotic nondisjunction, contrary to the commonly reported mechanism of mitotic recombination. Keywords: homozygous KIT mutation; GIST; SNP Gastrointestinal stromal tumors (GISTs) originate from the interstitial cells of Cajal and are driven by a proliferative signal resulting from dominant activating mutations of KIT or platelet-derived growth factor receptor-a (PDGFRA).

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Section: Discussionsupporting

confidence: 79%

Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression

et al. 2008

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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%

“…As described above, various types of exon 11 germline c-kit gene mutations have been reported, 30,31,33,34,[36][37][38][39][40]43,44,46,49 but KIT-Tyr553Cys mutation has not been reported yet. Even in somatic c-kit gene mutation in sporadic GISTs, substitution of amino acid at codon 553 appears to be very rare.…”

Section: Familal Gists With Kit-tyr553cysmentioning

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.…”

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confidence: 99%

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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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“…Somatic mutations in the c-kit or platelet derived growth factor receptor A (PDGFRA) genes are frequently found in most GISTs, and are recognized as gatekeeper molecular events [1][2][3] . GIST generally occurs as a sporadic solitary neoplasm whereas the occurrence of multiple primary neoplasms is considered to be an exceptional event, restricted to Carney's syndrome [4] , pediatric GISTs [5] , type 1 neurofibromatosis (NF1)-associated GISTs [6][7][8] , familial GISTs [9,10] and multiple sporadic GISTs [10][11][12] . We herein report a case of twelve simultaneous sporadic GISTs in the small intestine that were successfully treated with surgical resection and were immunohistochemically examined and genetically analyzed the c-kit and PDGFRA mutations.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical and molecular genetic analyses of multiple sporadic gastrointestinal stromal tumors

Hiraki

Kitajima²,

Ohtsuka³

et al. 2010

WJGO

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A 77-year-old Japanese male patient was admitted to our hospital complaining of general fatigue and melena. A gastroduodenal endoscopic examination revealed no definitive localized lesions. However, both a large amount of cruor and blood flow from the small intestine into the ascending colon was observed during the colonoscopic examination. At least three tumors, believed to originate from the small intestine, were detected by abdominal computed tomography. Based on these findings, multiple and hemorrhagic small intestinal tumors were diagnosed and surgical treatment of the tumors planned. During the celiotomy, twelve tumors were found in the small intestine. Intestinal wedge or partial resection was applied. All excised specimens demonstrated morphology of a submucosal tumor and the largest tumor had a delle with coagulation on the mucosal face. In the histological findings, hematoxylin and eosin staining showed spindle cell morphology. The immunohistochemical examination revealed that the tumor cells were diffusely positive for KIT and CD34. The myenteric plexus layer of the small intestine was focal-positive for KIT and showed no intestinal cells of Cajal hyperplasia. The tumor sequencing results revealed an identical missense mutation in codon 642 of c-kit exon 13 leading to the replacement of lysine by glutamic acid and a silent germ-line mutation in exon 12 of the PDGFRA gene concerning whole blood, normal mucosa and tumors. We concluded that the current subject was categorized as having multiple sporadic-type gastrointestinal stromal tumor with identical mutational types. Although the patient did not receive any adjuvant chemotherapy, there has been no sign of recurrence over the 3 years since the surgery.

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Multiple gastrointestinal stromal tumors with a germline c‐kit mutation

Cited by 46 publications

References 19 publications

Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression

Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression

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

Immunohistochemical and molecular genetic analyses of multiple sporadic gastrointestinal stromal tumors

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