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

TY - JOUR

T1 - Characterization and validation of somatic mutation spectrum to reveal heterogeneity in gastric cancer by single cell sequencing

AU - Peng, Lihua

AU - Xing, Rui

AU - Liu, Dongbing

AU - Bao, Li

AU - Cheng, Wenxiang

AU - Wang, Hongyi

AU - Yu, Yuan

AU - Liu, Xiaofeng

AU - Jiang, Lu

AU - Wu, Yan

AU - An, Zhongxue

AU - Liang, Qiaoyi

AU - Kim, Ryong Nam

AU - Shin, Young Kee

AU - Yang, Huanming

AU - Wang, Jian

AU - Yu, Jun

AU - Zhang, Xiuqing

AU - Xu, Xun

AU - Yang, Jiaan

AU - Wu, Kui

AU - Zhu, Shida

AU - Lu, Youyong

PY - 2019/2/28

Y1 - 2019/2/28

N2 - 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.

AB - 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.

KW - Gastric cancer

KW - Heterogeneity

KW - Significant mutated gene

KW - Single-cell whole exome sequencing

KW - SNV

U2 - 10.1016/j.scib.2018.12.014

DO - 10.1016/j.scib.2018.12.014

M3 - Journal article

AN - SCOPUS:85060336011

SN - 2095-9273

VL - 64

SP - 236

EP - 244

JO - Science Bulletin

JF - Science Bulletin

IS - 4

ER -