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首页> 外文期刊>Cancer Medicine >Muscle RAS oncogene homolog ( MRAS ) recurrent mutation in Borrmann type IV gastric cancer
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Muscle RAS oncogene homolog ( MRAS ) recurrent mutation in Borrmann type IV gastric cancer

机译：Borrmann型IV型胃癌的肌RAS癌基因同源突变（MRAS）反复突变。

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Abstract The prognosis of patients with Borrmann type IV gastric cancer (Type IV) is extremely poor. Thus, there is an urgent need to elucidate the molecular mechanisms underlying the oncogenesis of Type IV and to identify new therapeutic targets. Although previous studies using whole-exome and whole-genome sequencing have elucidated genomic alterations in gastric cancer, none has focused on comprehensive genetic analysis of Type IV. To discover cancer-relevant genes in Type IV, we performed whole-exome sequencing and genome-wide copy number analysis on 13 patients with Type IV. Exome sequencing identified 178 somatic mutations in protein-coding sequences or at splice sites. Among the mutations, we found a mutation in muscle RAS oncogene homolog ( MRAS ), which is predicted to cause molecular dysfunction. MRAS belongs to the Ras subgroup of small G proteins, which includes the prototypic RAS oncogenes. We analyzed an additional 46 Type IV samples to investigate the frequency of MRAS mutation. There were eight nonsynonymous mutations (mutation frequency, 17%), showing that MRAS is recurrently mutated in Type IV. Copy number analysis identified six focal amplifications and one homozygous deletion, including insulin-like growth factor 1 receptor ( IGF1R ) amplification. The samples with IGF1R amplification had remarkably higher IGF1R mRNA and protein expression levels compared with the other samples. This is the first report of MRAS recurrent mutation in human tumor samples. Our results suggest that MRAS mutation and IGF1R amplification could drive tumorigenesis of Type IV and could be new therapeutic targets.
机译：摘要IV型Borrmann胃癌患者的预后极差。因此，迫切需要阐明IV型肿瘤发生的分子机制并确定新的治疗靶标。尽管先前使用全外显子组和全基因组测序的研究阐明了胃癌的基因组改变，但没有研究集中在IV型的全面遗传分析上。为了发现IV型中与癌症相关的基因，我们对13位IV型患者进行了全外显子组测序和全基因组拷贝数分析。外显子组测序在蛋白质编码序列或剪接位点鉴定出178个体细胞突变。在这些突变中，我们发现了肌肉RAS癌基因同源物（MRAS）中的一个突变，该突变预计会导致分子功能障碍。 MRAS属于小G蛋白的Ras子组，其中包括原型RAS癌基因。我们分析了另外46个IV型样本，以调查MRAS突变的频率。有八个非同义突变（突变频率为17％），表明MRAS在IV型中反复突变。拷贝数分析确定了6个局灶扩增和1个纯合缺失，包括胰岛素样生长因子1受体（IGF1R）扩增。与其他样品相比，具有IGF1R扩增的样品的IGF1R mRNA和蛋白表达水平明显更高。这是人类肿瘤样品中MRAS复发突变的首次报道。我们的结果表明，MRAS突变和IGF1R扩增可以驱动IV型肿瘤的发生，并可能成为新的治疗靶点。

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