Pediatric Mastocytosis Is a Clonal Disease Associated with D816V and Other Activating c-KIT Mutations
Pediatric Mastocytosis Is a Clonal Disease Associated with D816V and Other Activating c-KIT Mutations
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DOI：
10.1038/jid.2009.281
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发表时间：
2010-03-01
影响因子：
6.5
通讯作者：
Dubreuil, Patrice
中科院分区：
文献类型：
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作者：
Bodemer, Christine;Hermine, Olivier;Dubreuil, Patrice
成人肥大细胞增多症是一种与c-KIT突变相关的不可治愈的克隆性疾病，主要发生在外显子17（（DV）-V-816）。相比之下，儿童肥大细胞增多症往往自发消退，被认为是一种反应性疾病。以前关于儿童肥大细胞增多症的研究只评估了少数患者，主要集中在密码子816突变上，结果各不相同。在这项研究中，我们分析了整个c-KIT序列从皮肤活检的50名儿童肥大细胞增多症（年龄0-16岁）。在42%的病例中发现密码子816（外显子17）突变，在44%的病例中观察到外显子17以外的突变。出乎意料的是，一半的突变位于c-KIT胞外结构域的第五个IG环，该结构域由外显子8和9编码。本研究中鉴定的所有突变均为体细胞突变，并导致c-KIT的组成性激活。没有明确的表型-基因型相关性，突变与家族性与自发性疾病之间没有明确的关系，c-KIT GNNK+和GNNK亚型的相对表达没有显著变化。这些发现有力地支持了这样一种观点，即尽管儿童肥大细胞增多症可以自发消退，但它是一种克隆性疾病，最常见的与c-KIT的激活突变有关
Adult mastocytosis is an incurable clonal disease associated with c-KIT mutations, mostly in exon 17 ((DV)-V-816). In contrast, pediatric mastocytosis often spontaneously regresses and is considered a reactive disease. Previous studies on childhood mastocytosis assessed only a few patients and focused primarily on codon 816 mutations, with various results. In this study, we analyzed the entire c-KIT sequence from cutaneous biopsies of 50 children with mastocytosis (ages 0-16 years). A mutation of codon 816 (exon 17) was found in 42% of cases, and mutations outside exon 17 were observed in 44%. Unexpectedly, half of the mutations were located in the fifth Ig loop of c-KIT's extracellular domain, which is encoded by exons 8 and 9. All mutations identified in this study were somatic and caused a constitutive activation of c-KIT. There was no clear phenotype-genotype correlation, no clear relationship between the mutations and familial versus spontaneous disease, and no significant change in the relative expression of the c-KIT GNNK+ and GNNK isoforms. These findings strongly support the idea that, although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with activating mutations in c-KIT