Familial gastrointestinal stromal tumor with germ line mutation of the juxtamembrane domain of the KIT gene observed in relatively young women

Tanida, Nobuyuki; Hirota, Seiichi; Daum, Ondřej; Hes, Ondřej; Michal, Michal; Lee, Gang-Hong

doi:10.1016/j.anndiagpath.2010.05.003

Cited by 14 publications

(8 citation statements)

References 26 publications

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“…2 Patients and families with these genomic alterations frequently develop multiple benign and malignant tumors. However, these syndromes account for only approximately 5% of GISTs [2][3][4][5][6] ; the remaining 95% are considered sporadic.…”

Section: Introductionmentioning

confidence: 99%

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population‐based study

Murphy

Grace

Baumgartner

et al. 2015

Cancer

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Purpose Most gastrointestinal stromal tumors (GIST) are considered non-hereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies with increased frequencies. We hypothesized that we could gain greater insight into possible associations between GIST and other malignancies using a national cancer database inquiry. Methods Patients diagnosed with GIST (2001–2011) in the Surveillance, Epidemiology, and End Results database were included. Standardized prevalence ratios (SPRs) and standardized incidence ratios (SIRs) were used to quantify cancer risks incurred by GIST patients before and after GIST diagnoses, respectively, when compared with the general U.S. population. Results Of 6,112 GIST patients, 1,047 (17.1%) had additional cancers. There were significant increases in overall cancer rates: 44% (SPR=1.44) before diagnosis and 66% (SIR=1.66) after GIST diagnoses. Malignancies with significantly increased occurrence both before/after diagnoses included other sarcomas (SPR=5.24/SIR=4.02), neuroendocrine-carcinoid tumors (SPR=3.56/SIR=4.79), non-Hodgkin’s lymphoma (SPR=1.69/SIR=1.76), and colorectal adenocarcinoma (SPR=1.51/SIR=2.16). Esophageal adenocarcinoma (SPR=12.0), bladder adenocarcinoma (SPR=7.51), melanoma (SPR=1.46), and prostate adenocarcinoma (SPR=1.20) were significantly more common only before GIST. Ovarian carcinoma (SIR=8.72), small intestine adenocarcinoma (SIR=5.89), papillary thyroid cancer (SIR=5.16), renal cell carcinoma (SIR=4.46), hepatobiliary adenocarcinomas (SIR=3.10), gastric adenocarcinoma (SIR=2.70), pancreatic adenocarcinoma (SIR=2.03), uterine adenocarcinoma (SIR=1.96), non-small cell lung cancer (SIR=1.74), and transitional cell carcinoma of the bladder (SIR=1.65) were significantly more common only after GIST. Conclusion This is the first population-based study to characterize the associations and temporal relationships between GIST and other cancers, both by site and histological type. These associations may carry important clinical implications for future cancer screening and treatment strategies.

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Section: Introductionmentioning

confidence: 99%

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population‐based study

Murphy

Grace

Baumgartner

et al. 2015

Cancer

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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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“…In patients with familial GISTs, germline mutations are located in this region of the KIT gene (21). Furthermore, germline and missense mutations at exon 11 in the juxtamembrane domain of the KIT gene were observed in a 25-year-old Japanese woman with familial GISTs (22). Therefore, exon 11 of KIT gene is a "hot spot" in both sporadic and familial GISTs, although less than 5% occur as part of hereditary familial or idiopathic multitumor syndromes.…”

Section: Gene Mutation In the Tumorigenesis Of Gastrointestinal Strommentioning

confidence: 99%

KIT gene mutations in gastrointestinal stromal tumor

Kang¹,

Zhu²,

et al. 2015

Front Biosci

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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. It arises in the stomach, small intestine, colon, rectum and esophagus. KIT gene mutation is a feature of GIST, in addition to PDGFRA gene mutation. KIT gene mutations have been observed to be involved in the development of GIST, its recurrence after surgery and chemotherapy resistance in GIST. Exons 13, 17, 9, and mainly exon 11 are concerned in these biological behaviors of GIST. In this review, we will discuss on the involvement of KIT gene mutations in the tumorigenesis, recurrence and chemotherapeutic resistance of GIST.

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Familial gastrointestinal stromal tumor with germ line mutation of the juxtamembrane domain of the KIT gene observed in relatively young women

Cited by 14 publications

References 26 publications

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population‐based study

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population‐based study

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

KIT gene mutations in gastrointestinal stromal tumor

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