Novel Germline Mutation of KIT Associated With Familial Gastrointestinal Stromal Tumors and Mastocytosis

Hartmann, Karin; Wardelmann, Eva; Ma, Yongsheng; Merkelbach‐Bruse, Sabine; Preussner, Liane M.; Woolery, Carla; Baldus, Stephan; Heinicke, Thomas; Thiele, Jüergen; Buettner, Reinhard; Longley, B. Jack

doi:10.1053/j.gastro.2005.06.060

Cited by 165 publications

(126 citation statements)

References 26 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…The aforementioned mutations in the exons 8 and 9 have have been reported in CBF-AML (D417-419insY) [40,41], kindreds with familial GISTs and mastocytosis (D 419) [42], familial mastocytosis (K509I) [43], and GISTs (ITD AY502-503) [44]. As with KITD816V, every one of the mutations in exons 8 and 9 that was tested was found to constitutively activate KIT kinase activity.…”

Section: Pardananimentioning

confidence: 86%

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Pardanani

2015

American J Hematol

View full text Add to dashboard Cite

Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs.Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V.Risk stratification: The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non‐MC lineage disease (SM‐AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis.Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom‐directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease‐related organ dysfunction; interferon‐α (+/−corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator‐release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib‐sensitive KIT mutation or in KITD816‐unmutated patients. Treatment of SM‐AHNMD is governed primarily by the non‐MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases.Investigational Drugs: Recent data confirms midostaurin's significant anti‐MC activity in patients with advanced SM. Am. J. Hematol. 90:251–262, 2015. © 2015 Wiley Periodicals, Inc.

show abstract

Section: Pardananimentioning

confidence: 86%

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Pardanani

2015

American J Hematol

View full text Add to dashboard Cite

show abstract

“…In contrast to sporadic gastrointestinal tumors that present with a single primary tumor, surgical intervention performed on an individual with a hereditary GIST may reveal tens to hundreds of tumor nodules. 3,5,7,[9][10][11][12][30][31][32] The mitotic rate of the tumors in most of these families (those who were documented) appear to be low suggesting that these tumors appear indolent compared with sporadic GIST. 3,9,10,12,13,30,33 Interestingly, 2 patients in our study presented with metastases at diagnosis despite displaying variable mitotic rates (1 with 5 mitoses per 50 hpf and 1 with 30 mitoses per 50 hpf.…”

Section: Discussionmentioning

confidence: 97%

“…In GIST kindreds, tumor nodules are often contiguous with areas of hyperplastic ICCs on histopathologic analysis 3,4,9,10,12,30,31,36 suggesting that these tumors arise within the hyperplastic ICC. In our study, the tumor nodules appeared to arise from a background of a hyperplastic Auerbach's plexus in the small bowel (Figs.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

Kleinbaum

Lazar

Tamborini

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Novel Germline Mutation of KIT Associated With Familial Gastrointestinal Stromal Tumors and Mastocytosis

Cited by 165 publications

References 26 publications

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

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

Contact Info

Product

Resources

About