SDHA Loss-of-Function Mutations in KIT-PDGFRA Wild-Type Gastrointestinal Stromal Tumors Identified by Massively Parallel Sequencing
SDHA Loss-of-Function Mutations in KIT-PDGFRA Wild-Type Gastrointestinal Stromal Tumors Identified by Massively Parallel Sequencing
复制标题
DOI：
10.1093/jnci/djr130
复制
发表时间：
2011-06-01
期刊：
影响因子：
--
通讯作者：
Biasco, Guido
中科院分区：
文献类型：
--
作者：
Pantaleo, Maria A.;Astolfi, Annalisa;Biasco, Guido
大约10%-15%的成人胃肠道间质瘤(GIST)在KIT或PDGFRA基因(即KIT/PDGFRA野生型GIST)中不存在任何突变。最近，在KIT/PDGFRA野生型GIST中发现了SDHB和SDHC(分别编码琥珀酸脱氢酶B和C亚基)的突变，而不是SDHA和SDHD(分别编码A和D亚基)的突变。为了寻找新的致病突变，我们使用大规模平行测序的方法对两名患有散发性KIT/PDGFRA野生型GIST的年轻成年患者的肿瘤转录组进行了测序。通过计算分析确定的唯一与疾病相关的变异是SDHA。1例携带p.Ser384X纯合子无义突变，另1例为复合杂合子携带p.Arg31X无义突变和p.Arg589Trp错义突变。这两个患者的杂合性无义突变都存在于从外周血中提取的生殖系DNA中。蛋白质结构分析表明，这三种突变都会导致蛋白质的功能失活。据我们所知，这是第一个将SDHA失活确定为GIST中常见致癌事件的报告，该事件在KIT和PDGFRA中缺乏突变。
Approximately 10%-15% of gastrointestinal stromal tumors (GISTs) in adults do not harbor any mutation in the KIT or PDGFRA genes (ie, KIT/PDGFRA wild-type GISTs). Recently, mutations in SDHB and SDHC (which encode succinate dehydrogenase subunits B and C, respectively) but not in SDHA and SDHD (which encode subunits A and D, respectively) were identified in KIT/PDGFRA wild-type GISTs. To search for novel pathogenic mutations, we sequenced the tumor transcriptome of two young adult patients who developed sporadic KIT/PDGFRA wild-type GISTs by using a massively parallel sequencing approach. The only variants identified as disease related by computational analysis were in SDHA. One patient carried the homozygous nonsense mutation p.Ser384X, the other patient was a compound heterozygote harboring a p.Arg31X nonsense mutation and a p.Arg589Trp missense mutation. The heterozygous nonsense mutations in both patients were present in germline DNA isolated from peripheral blood. Protein structure analysis indicates that all three mutations lead to functional inactivation of the protein. This is the first report, to our knowledge, that identifies SDHA inactivation as a common oncogenic event in GISTs that lack a mutation in KIT and PDGFRA.