Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case.
Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case.
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DOI：
10.1186/s12885-015-1872-y
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发表时间：
2015-11-10
期刊：
影响因子：
3.8
通讯作者：
von Mehren M
中科院分区：
文献类型：
--
作者：
Belinsky MG;Rink L;Cai KQ;Capuzzi SJ;Hoang Y;Chien J;Godwin AK;von Mehren M
大约 10-15% 的胃肠道间质瘤 (GIST) 缺乏 KIT 和血小板衍生生长因子受体 α (PDGFRA) 基因的功能突变。对于这些“野生型”GIST 的一个子集，已经确定了通过琥珀酸脱氢酶 (SDH) 酶复合物功能丧失而导致肿瘤发生的另一种机制。对来自 SDH 完整野生型 GIST 病例的配对肿瘤和正常 DNA 进行全外显子组测序，以确定该肿瘤的致病机制。通过 Sanger DNA 测序、定量实时 PCR 和免疫组织化学方法，对 GIST 肿瘤组中的选定结果进行了进一步研究。在患者的 GIST 中发现了神经纤维蛋白 1 (NF1) 基因中的半合移码突变 (p.His2261Leufs*4)；然而，没有发现种系 NF1 突变。还鉴定出 MYC 相关 X 因子 (MAX) 基因中的体细胞移码突变 (p.Lys54Argfs*31)。对大量 GIST 进行 MAX 免疫组织化学分析发现，在 MAX 突变的 GIST 和主要是 KIT 突变的肿瘤子集中，MAX 表达缺失。这项研究表明，神经纤维瘤病之外的 NF1 突变失活可能是散发性 GIST 的致癌机制。此外，首次在 GIST 中发现了 MAX 基因的功能丧失突变，并提示 MAX 在 GIST 进展中发挥更广泛的作用。本文的在线版本 (doi:10.1186/s12885-015-1872-y) 包含补充材料，可供授权用户使用。
Approximately 10–15 % of gastrointestinal stromal tumors (GISTs) lack gain of function mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. An alternate mechanism of oncogenesis through loss of function of the succinate-dehydrogenase (SDH) enzyme complex has been identified for a subset of these “wild type” GISTs. Paired tumor and normal DNA from an SDH-intact wild-type GIST case was subjected to whole exome sequencing to identify the pathogenic mechanism(s) in this tumor. Selected findings were further investigated in panels of GIST tumors through Sanger DNA sequencing, quantitative real-time PCR, and immunohistochemical approaches. A hemizygous frameshift mutation (p.His2261Leufs*4), in the neurofibromin 1 (NF1) gene was identified in the patient’s GIST; however, no germline NF1 mutation was found. A somatic frameshift mutation (p.Lys54Argfs*31) in the MYC associated factor X (MAX) gene was also identified. Immunohistochemical analysis for MAX on a large panel of GISTs identified loss of MAX expression in the MAX-mutated GIST and in a subset of mainly KIT-mutated tumors. This study suggests that inactivating NF1 mutations outside the context of neurofibromatosis may be the oncogenic mechanism for a subset of sporadic GIST. In addition, loss of function mutation of the MAX gene was identified for the first time in GIST, and a broader role for MAX in GIST progression was suggested. The online version of this article (doi:10.1186/s12885-015-1872-y) contains supplementary material, which is available to authorized users.