Approximately half of the world's 500,000 new oesophageal squamous-cell carcinoma (ESCC) cases each year occur in China. Here, we show whole-genome sequencing of DNA and RNA in 94 Chinese individuals with ESCC. We identify six mutational signatures (E1–E6), and Signature E4 is unique in ESCC linked to alcohol intake and genetic variants in alcohol-metabolizing enzymes. We discover significantly recurrent mutations in 20 protein-coding genes, 4 long non-coding RNAs and 10 untranslational regions. Functional analyses show six genes that have recurrent copy-number variants in three squamous-cell carcinomas (oesophageal, head and neck and lung) significantly promote cancer cell proliferation, migration and invasion. The most frequently affected genes by structural variation are LRP1B and TTC28. The aberrant cell cycle and PI3K-AKT pathways seem critical in ESCC. These results establish a comprehensive genomic landscape of ESCC and provide potential targets for precision treatment and prevention of the cancer.
Esophageal squamous-cell carcinoma (ESCC), one of the most prevalent and lethal malignant disease, has a complex but unknown tumor ecosystem. Here, we investigate the composition of ESCC tumors based on 208,659 single-cell transcriptomes derived from 60 individuals. We identify 8 common expression programs from malignant epithelial cells and discover 42 cell types, including 26 immune cell and 16 nonimmune stromal cell subtypes in the tumor microenvironment (TME), and analyse the interactions between cancer cells and other cells and the interactions among different cell types in the TME. Moreover, we link the cancer cell transcriptomes to the somatic mutations and identify several markers significantly associated with patients’ survival, which may be relevant to precision care of ESCC patients. These results reveal the immunosuppressive status in the ESCC TME and further our understanding of ESCC.
Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8
+
response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed.
Esophageal squamous-cell carcinoma (ESCC) is one of the most lethal malignancies in the world and occurs at particularly higher frequency in China. While several genome-wide association studies (GWAS) of germline variants and whole-genome or whole-exome sequencing studies of somatic mutations in ESCC have been published, there is no comprehensive database publically available for this cancer. Here, we developed the Chinese Cancer Genomic Database-Esophageal Squamous Cell Carcinoma (CCGD-ESCC) database, which contains the associations of 69,593 single nucleotide polymorphisms (SNPs) with ESCC risk in 2022 cases and 2039 controls, survival time of 1006 ESCC patients (survival GWAS) and gene expression (expression quantitative trait loci, eQTL) in 94 ESCC patients. Moreover, this database also provides the associations between 8833 somatic mutations and survival time in 675 ESCC patients. Our user-friendly database is a resource useful for biologists and oncologists not only in identifying the associations of genetic variants or somatic mutations with the development and progression of ESCC but also in studying the underlying mechanisms for tumorigenesis of the cancer. CCGD-ESCC is freely accessible at http://db.cbi.pku.edu.cn/ccgd/ESCCdb.
Adenocarcinoma at the gastroesophageal junction (ACGEJ) has dismal clinical outcomes, and there are currently few specific effective therapies because of limited knowledge on its genomic and transcriptomic alterations. The present study investigates genomic and transcriptomic changes in ACGEJ from Chinese patients and analyzes their drug vulnerabilities and associations with the survival time. Here we show that the major genomic changes of Chinese ACGEJ patients are chromosome instability promoted tumorigenic focal copy-number variations and COSMIC Signature 17-featured single nucleotide variations. We provide a comprehensive profile of genetic changes that are potentially vulnerable to existing therapeutic agents and identify Signature 17-correlated IFN-α response pathway as a prognostic marker that might have practical value for clinical prognosis of ACGEJ. These findings further our understanding on the molecular biology of ACGEJ and may help develop more effective therapeutic strategies.
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