全基因组水平鉴定食管鳞癌驱动CNVs及其机制研究

食管鳞癌（ESCC）是我国特色的高发恶性肿瘤，高异质性使其发病机理极其复杂，致使临床缺乏有效诊断和治疗手段。申请者前期对我国ESCC患者进行了大样本全基因组测序分析，发现拷贝数变异（CNVs）在ESCC发生发展过程中发挥重要作用。但迄今为止尚缺乏大样本全基因组水平筛选驱动CNVs。本项目拟在前期735例ESCC全基因组测序数据基础上，①聚类分析获得CNVs亚型，并与临床信息进行相关性分析，有望鉴定出潜在的有临床应用价值的CNVs或靶基因；②采用CRISPR/Cas9技术，筛选前期大样本CNVs分析获得的候选基因，并进行功能验证和机制研究，获得候选靶向治疗靶点；③结合OncoKB数据库，筛选现有靶向药物的靶基因，并进行疗效评估。本项目从全基因组水平系统筛选ESCC演进过程中驱动CNVs，并阐明其致癌机理，可为筛选ESCC早诊、分子分型以及预后标记物、研发新药和指导临床个体化治疗提供依据。

Esophageal squamous cell carcinoma (ESCC) constitutes the predominant histology of esophageal cancer in China and has limited therapeutic options. Intra- or inter-tumor heterogeneity (ITH) contribute to the complexity tumorigenesis of ESCC. We previously performed whole-genome sequencing on 735 pairs of ESCC tumors and matched adjacent non-cancerous esophagus tissues (735-WGS). Interestingly, we found copy number variations (CNVs) exhibited critical roles in initiation and development of ESCC. Unfortunately, there is no study focusing on screening driver CNVs across ESCC genomes. In this study, we will perform cluster analysis based on the 735-WGS data to screen drive CNVs and discover clinical predicators. Using CRISPR/Cas9 system, we will identify CNVs-derived cancer-associated genes and explore the underlying mechanism via in vitro and in vivo studies. The goal of this project is to identify diagnostic/prognostic biomarkers and potential therapeutic targets for ESCC patients.