A germline mutation in KIT in familial diffuse cutaneous mastocytosis

Tang, Xiao-li; Boxer, M.; Drummond, A.; Ogston, P; Hodgins, Malcolm B.; Burden, A. D.

doi:10.1136/jmg.2003.015156

Cited by 87 publications

(76 citation statements)

References 20 publications

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“…The sites and types of these mutations maintain receptors KIT and PDGFRA constitutively activated in GIST, as previously reported. Mutations in other exons of c-kit are responsible for the constitutive enzymatic activation of KIT in other diseases (44)(45)(46)(47)(48)(49). Our results contribute to understanding the incidence of mutant forms of c-kit and pdgfra in patients with GIST, and have helped us lay the foundations for personalized cancer medicine in Panama.…”

Section: Discussionmentioning

confidence: 95%

Beginning of personalized medicine in Panama: Molecular and pathological characteristics of gastrointestinal stromal tumors from archival paraffin-embedded tissue

et al. 2011

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Abstract. This is the first study from Central America to analyze genetic mutations and histopathological features associated with gastrointestinal stromal tumors (GIST). Mutations found in the tyrosine kinase membrane receptors c-kit and pdgfra are associated with clinical and pathological characteristics of GIST. New drugs that inhibit the expression of these oncogenes at the molecular level substantially improve the quality of life for patients with this tumor. It is therefore essential for patient care in Panama that genetic analysis of GIST tumors continues to develop from the pilot study presented herein into routine clinical use. This study evaluated 39 cases of GIST in Panama, using samples archived at the Instituto Oncológico Nacional from 1994 to 2004. DNA from paraffin-embedded tumor tissues was isolated and amplified for the exons of c-kit and pdgfra associated with a high frequency of mutations. Direct PCR sequencing of specific exons was performed, and those with different alleles were cloned and re-sequenced. Amino acid sequences were inferred from DNA and aligned to Genbank reference sequences to determine the position and type of mutation. The highest frequency of mutations was found in exon 11 of the c-kit gene (70%). Mutations found in this exon were heterogeneous, while only one type of mutation (p.A502_Y503dup) was observed in c-kit exon 9. Mutations in the pdgfra gene constituted several substitutions, with the deletion p.D842V being observed most frequently. The observed GIST-associated mutations were previously described. Four patients with mutations associated with familial GIST were also found. The majority (66%) of patients with mutations in exon 11 (residues 550-591) were considered to be at high risk and 75% of patients with mutations specifically within residues 556-560 (exon 11) were considered to have high-risk GIST. This is the first molecular study of GIST in Central America. It was performed to gain a better understanding of the cancer-associated mutations of KIT and platelet-derived growth factor receptor α (PDGFRA) receptors. This may aid in the prediction of clinical evolution and guide the use of specific drug treatments in patients with GIST in Panama.

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Section: Discussionmentioning

confidence: 95%

Beginning of personalized medicine in Panama: Molecular and pathological characteristics of gastrointestinal stromal tumors from archival paraffin-embedded tissue

et al. 2011

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“…This contradiction is confirmed by the observation that germline mutations have been observed with ECD or TMD mutants but not with PTD mutants. 4,5,14 Globally, it seems that ECD mutations are not fully transforming in human MCs, contrasting with their high oncogenic potential in Cajal cells that can give rise to GIST. This could be explained by a difference in cell-specific signaling, either through selective expression of positive regulator(s) in Cajal cell lineage or via a negative regulation pathway only in MC lineage.…”

Section: Differences In Functional Activity Between Ptd and Ecd Mutantsmentioning

confidence: 99%

“…3 Although it is a sporadic disease, rare family cases have been reported. 4,5 In the past decade, increasing evidence has demonstrated that the development of mastocytosis is linked to gain of function (GOF) of the c-kit proto-oncogene. [6][7][8] The c-kit gene encodes the stem cell factor (SCF) receptor, KIT, which belongs to the subclass III of the tyrosine kinase receptor family.…”

Section: Introductionmentioning

confidence: 99%

Pediatric mastocytosis–associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations

Yang

Letard

Borge

et al. 2010

Blood

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Compared with adults, pediatric mastocytosis has a relatively favorable prognosis. Interestingly, a difference was also observed in the status of c-kit mutations according to the age of onset. Although most adult patients have a D 816 V mutation in phosphotransferase domain (PTD), we have described that half of the children carry mutations in extracellular domain (ECD). KIT-ECD versus KIT-PTD mutants were introduced into rodent Ba/F3, EML, Rat2, and human TF1 cells to investigate their biologic effect. Both ECD and PTD mutations induced constitutive receptor autophosphorylation and ligandindependent proliferation of the 3 hematopoietic cells. Unlike ECD mutants, PTD mutants enhanced cluster formation and up-regulated several mast cell-related antigens in Ba/F3 cells. PTD mutants failed to support colony formation and erythropoietin-mediated erythroid differentiation. ECD and PTD mutants also displayed distinct whole-genome transcriptional profiles in EML cells. We observed differences in their signaling properties: they both activated STAT, whereas AKT was only activated by ECD mutants. Consistently, AKT inhibitor suppressed ECD mutant-dependent proliferation, clonogenicity, and erythroid differentiation. Expression of myristoylated AKT restored erythroid differentiation in EML-PTD cells, suggesting the differential role of AKT in those mutants. Overall, our study implied different pathogenesis of pediatric versus adult mastocytosis, which might explain their diverse phenotypes. (Blood.

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“…[1][2][3][4][5][6][7][8][9] Typically, the A71763T substitution is detected, whereby an aspartate is changed for a valine at codon 816 of the c-kit protein sequence. However, other uncommon somatic (V560G, 10 D815K, 11 D816Y, 2,11,12 D816F, 2,11 D816H, 13 and D820G 14 ) and germ-line (F522C, 15 A533D, 16 K509I, 17 and del419 18 ) mutations, which may result in a ligand-independent activation of the stem cell factor receptor, have been reported, most frequently in individual cases. Presence of the KIT mutations in patients with systemic mastocytosis (SM) is not restricted to BM MCs, but it has also been sporadically reported in other non-MC hematopoietic lineages, 7,[19][20][21][22][23][24] suggesting that expansion of clonal MCs may arise from an uncommitted hematopoietic stem cell.…”

Section: Introductionmentioning

confidence: 99%

KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients

Garcia-Montero

Jara‐Acevedo

Teodósio

et al. 2006

Blood

442

480

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Despite the relevance of the c-kit/stem cell factor (SCF) signaling pathway in mast cell (MC) diseases, the exact frequency of KIT mutations in different compartments of bone marrow (BM) hematopoietic cells of individuals with systemic mastocytosis (SM), and its different diagnostic categories, remains unknown. In this study, we prospectively analyzed the presence of KIT mutations in fluorescence-activated cell-sorting (FACS)-purified populations of BM MCs (n ‫؍‬ 113) and other BM cell compartments (n ‫؍‬ 67) from adults with SM. Our results show the presence of D816V KIT mutation in virtually all adults (93%) with indolent and aggressive forms of SM, except welldifferentiated SM (29%), while other KIT mutations were rarely (< 3%) detected. In around one-third of patients with mutated MCs, the KIT mutation was also detected in CD34 ؉ hematopoietic cells and eosinophils, and, to a lesser extent, in monocytic, neutrophil-lineage BM precursor cells and lymphocytes. Most patient with poor-prognosis SM (81%) carried the KIT mutation in 2 or more BM myeloid cell populations, while this was detected in a smaller proportion (27%) of indolent cases. These results would support the notion that KIT mutation is a hallmark of adult SM where it targets a pluripotent hematopoietic stem cell, and may contribute to explaining previously observed discrepancies in the literature. IntroductionMast cell diseases (MCDs) are a heterogeneous group of disorders characterized by an abnormal proliferation and accumulation of mast cells (MCs) in different tissues. In a relatively high proportion of cases, the clonal nature of the disease can be established on the basis of the demonstration of gain-of-function mutations involving the tyrosine kinase domain of c-kit in lesional skin and bone marrow (BM) cells. [1][2][3][4][5][6][7][8][9] Typically, the A71763T substitution is detected, whereby an aspartate is changed for a valine at codon 816 of the c-kit protein sequence. However, other uncommon somatic (V560G, 10 D815K, 11 D816Y, 2,11,12 D816F, 2,11 D816H, 13 and D820G 14 ) and germ-line (F522C, 15 A533D, 16 K509I, 17 and del419 18 ) mutations, which may result in a ligand-independent activation of the stem cell factor receptor, have been reported, most frequently in individual cases. Presence of the KIT mutations in patients with systemic mastocytosis (SM) is not restricted to BM MCs, but it has also been sporadically reported in other non-MC hematopoietic lineages, 7,[19][20][21][22][23][24] suggesting that expansion of clonal MCs may arise from an uncommitted hematopoietic stem cell. However, attempts to demonstrate the presence of KIT mutation in purified CD34 ϩ hematopoietic precursor cells have failed so far. 25 The pathogenetic relevance of the different KIT mutations in MCDs is still not fully understood; however, their identification has become of major prognostic significance 26 due to the availability of protein kinase inhibitors such as imatinib (STI571, Gleevec; Novartis, Basel, Switzerland). These new targeted drugs hav...

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A germline mutation in KIT in familial diffuse cutaneous mastocytosis

Cited by 87 publications

References 20 publications

Beginning of personalized medicine in Panama: Molecular and pathological characteristics of gastrointestinal stromal tumors from archival paraffin-embedded tissue

Beginning of personalized medicine in Panama: Molecular and pathological characteristics of gastrointestinal stromal tumors from archival paraffin-embedded tissue

Pediatric mastocytosis–associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations

KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients

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