Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients
Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients
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DOI：
10.1093/hmg/ddl016
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发表时间：
2006-03-15
影响因子：
3.5
通讯作者：
Legius, E
中科院分区：
文献类型：
--
作者：
Maertens, O;Prenen, H;Legius, E
胃肠道间质瘤（GIST）是胃肠道最常见的间叶性肿瘤。KIT和PDGFRA激活突变是大多数散发性GIST的致癌机制。除了零星发生外，越来越多的人认识到GIST与1型神经纤维瘤病（NF 1）有关，但其潜在的致病机制仍然难以捉摸。为了深入了解NF 1患者GIST形成的机制，我们研究了来自3名NF 1患者的7个GIST，并结合了不同的技术：突变分析（KIT，PDGFRA和NF 1），蛋白质印迹，阵列CGH和离体伊马替尼反应实验。我们证明：（i）NF 1相关GIST不具有KIT或PDGFRA突变，（ii）该患者组中GIST发展的潜在分子事件是肿瘤中野生型NF 1等位基因的体细胞失活，以及（iii）神经纤维蛋白的失活是（超）激活MAP激酶途径的替代机制，而与散发性GIST相比，在NF 1相关GIST中JAK-STAT 3和PI 3 K-AKT通路的激活较少。总之，我们首次报道了NF 1个体中GIST的分子发病机制，并证明这种类型的肿瘤显然属于NF 1的临床症状谱。
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.