Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer
Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer
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DOI：
10.1038/ng.2983
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发表时间：
2014-06-01
期刊：
影响因子：
30.8
通讯作者：
Leung, Suet Yi
中科院分区：
文献类型：
--
作者：
Wang, Kai;Yuen, Siu Tsan;Leung, Suet Yi
胃癌是一种具有不同分子和组织亚型的异质性疾病。我们对100对肿瘤-正常配对进行了全基因组测序，以及DNA拷贝数、基因表达和甲基化图谱，以进行综合基因组分析。我们发现了亚型特有的遗传和表观遗传扰动以及独特的突变特征。我们鉴定了已知的(TP53、ARID1A和CDH1)和新的(MUC6、CTNNA2、GLI3、RNF43等)显著突变的驱动基因。具体地说，我们在14.3%的弥漫型肿瘤中发现了RHOA突变，但在肠型肿瘤中没有发现(P<；0.001)。这些突变聚集在反复出现的影响功能结构域的热点上，并导致RHOA信号缺陷，促进了有机物培养中的失巢凋亡逃逸。胃癌中最常见的干扰途径包括粘着连接和局灶粘着，其中RHOA和我们发现的其他突变基因作为关键角色参与其中。这些发现展示了一个多维和全面的基因组图景，突出了胃癌的分子复杂性，并为促进基因组引导的个性化治疗提供了路线图。
Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.