early-ESCC sequencing study

We performed a comprehensive multi-omics analysis of 756 trace-tumor-samples from 124 esophageal squamous cell carcinoma phase (ESCC) patients, covering 9 histopathological stages in 3 phases as nontumor phase (NT phase), intraepithelial neoplasia phase (IEN phase), and ESCC phase. Proteogenomics elucidated the stage-specific molecular characterization and defined the cancer-driving waves along with the mutation accumulation in EC progression. The integrated multi-omics uncovered the chromosome 3q gain was the key event in the transmit from the NT to IEN phase, disclosed the top mutation of TP53 enhanced cell cycle and DNA replication in the IEN phase, and revealed the ESCC phase mutations of AKAP9 and MCAF1 elevated glycolysis and Wnt signaling, respectively. Furthermore, the trajectory analysis identified 6 major tracks related to different clinical features during ESCC progression. Growingly enhanced and hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) was detected and considered as a drug target in ESCC progression. Collectively, this study provides insight into the understanding of ESCC molecular mechanism and a valuable resource for the development of therapeutic targets.EGA study EGAS00001006126我们对124例食管鳞状细胞癌（esophageal squamous cell carcinoma, ESCC）患者的756份微量肿瘤样本开展了全面的多组学分析，涵盖3个阶段共计9种组织病理学分期，分别为非肿瘤阶段（nontumor phase, NT phase）、上皮内瘤变阶段（intraepithelial neoplasia phase, IEN phase）与ESCC阶段。蛋白质基因组学（proteogenomics）阐明了各阶段特异性的分子特征，明确了食管癌进展过程中的致癌驱动波次与突变积累规律。整合多组学分析揭示，3号染色体长臂（3q）拷贝数获得是从NT阶段向IEN阶段转变的关键事件；研究发现TP53高频突变可增强IEN阶段的细胞周期与DNA复制过程；同时还揭示，ESCC阶段中AKAP9与MCAF1的突变分别上调了糖酵解与Wnt信号通路。此外，轨迹分析鉴定出ESCC进展过程中与不同临床特征相关的6条主要演进轨迹。研究检测到磷酸甘油酸激酶1（PGK1，S203位点）的表达持续上调且存在过度磷酸化，该蛋白被认定为ESCC进展中的潜在药物靶点。综上，本研究为解析ESCC的分子机制提供了全新视角，同时为治疗靶点的开发提供了极具价值的研究资源。本数据集对应的EGA研究编号为EGAS00001006126