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Characterization and validation of somatic mutation spectrum to reveal heterogeneity in gastric cancer by single cell sequencing

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Science Bulletin 2019年第4期64卷 236-244页

作者： Lihua Peng Rui Xing Dongbing Liu Li Bao Wenxiang Cheng Hongyi Wang Yuan Yu Xiaofeng Liu Lu Jiang Yan Wu Zhongxue An Qiaoyi Liang Ryong Nam Kim Young Kee Shin Huanming Yang Jian Wang Jun Yu Xiuqing Zhang Xun Xu Jiaan Yang Kui Wu Shida Zhu Youyong Lu BGI-Shenzhen China National GeneBank-Shenzhen BGI-Shenzhen Laboratory of Molecular Oncology Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Peking University Cancer Hospital & Institute Department of Drug Design and Pharmacology University of Copenhagen Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Department of Histology and Embryology Inner Mongolia Medical University Department of Medicine and Therapeutics State Key Laboratory of Digestive Disease Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences The Chinese University of Hong Kong Department of Pharmacy College of Pharmacy Seoul National University James D. Watson Institute of Genome Sciences Micro Pharmatech Ltd Department of Biology University of Copenhagen

Gastric cancer(GC) is a highly heterogeneous disease with multiple cellular types and poor ***, 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 singlenucleotide 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.

关键词： Gastric cancer single-cell whole exome sequencing SNV Signi-cell mutated gene Heterogeneity

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