Peng Lihua, Xing Rui, Liu Dongbing, Bao Li, Cheng Wenxiang, Wang Hongyi, Yu Yuan, Liu Xiaofeng, Jiang Lu, Wu Yan, An Zhongxue, Liang Qiaoyi, Kim Ryong Nam, Shin Young Kee, Yang Huanming, Wang Jian, Yu Jun, Zhang Xiuqing, Xu Xun, Yang Jiaan, Wu Kui, Zhu Shida, Lu Youyong
BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen 518083, China.
Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China.
Sci Bull (Beijing). 2019 Feb 28;64(4):236-244. doi: 10.1016/j.scib.2018.12.014. Epub 2018 Dec 15.
Gastric cancer (GC) is a highly heterogeneous disease with multiple cellular types and poor prognosis. However, the cellular evolution and molecular basis of GC at the individual intra-tumor level has not been well demonstrated. We performed single-cell whole exome sequencing to detect somatic single-nucleotide variants (SNVs) and significantly mutated genes (SMGs) among 34 tumor cells and 9 normal cells from a patient with GC. The Complete Prediction for Protein Conformation (CPPC) approach directly predicting the folding conformation of the protein 3D structure with Protein Folding Shape Code, combined with functional experiments were used to confirm the characterization of mutated SMGs in GC cells. We identified 201 somatic SNVs, including 117 non-synonymous mutations in GC cells. Further analysis identified 24 significant mutated genes (SMGs) in single cells, for which a single amino acid change might affect protein conformation. Among them, two genes (CDC27 and FLG) that were mutated only in single cells but not in the corresponding tumor tissue, were recurrently present in another GC tissue cohort, and may play a potential role to promote carcinogenesis, as confirmed by functional characterization. Our findings showed a mutational landscape of GC at intra-tumor level for the first time and provided opportunities for understanding the heterogeneity and individualized target therapy for this disease.
胃癌（GC）是一种具有多种细胞类型且预后较差的高度异质性疾病。然而，GC在个体肿瘤内水平的细胞进化和分子基础尚未得到充分阐明。我们对一名GC患者的34个肿瘤细胞和9个正常细胞进行了单细胞全外显子测序，以检测体细胞单核苷酸变异（SNV）和显著突变基因（SMG）。采用蛋白质折叠形状编码直接预测蛋白质三维结构折叠构象的完全蛋白质构象预测（CPPC）方法，并结合功能实验来确认GC细胞中突变SMG的特征。我们在GC细胞中鉴定出201个体细胞SNV，包括117个非同义突变。进一步分析在单细胞中鉴定出24个显著突变基因（SMG），单个氨基酸变化可能会影响其蛋白质构象。其中，有两个基因（CDC27和FLG）仅在单细胞中发生突变，而在相应肿瘤组织中未发生突变，在另一个GC组织队列中反复出现，功能表征证实它们可能在促进癌变过程中发挥潜在作用。我们的研究结果首次展示了GC在肿瘤内水平的突变图谱，并为理解该疾病的异质性和个体化靶向治疗提供了契机。
