Abstract
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.
Highlights
Half of the world’s 500,000 new oesophageal squamous-cell carcinoma (ESCC) cases each year occur in China
We found that the average percentage of the T4C mutation per sample was significantly higher in drinkers (13.6%) than in non-drinkers (9.7%; P 1⁄4 3.60 Â 10 À 10, unpaired t-test) and Signature E4, characterized by the T4C mutation, is similar to Catalogue of Somatic Mutations in Cancer (COSMIC) Signature 16 of which the origin was unknown before
We performed an integrative analysis of whole-genome sequencing (WGS) and RNA sequencing of 94 ESCC samples
Summary
Half of the world’s 500,000 new oesophageal squamous-cell carcinoma (ESCC) cases each year occur in China. Correspondence and requests for materials should be addressed to C.W. Oesophageal squamous-cell carcinoma (ESCC) ranks the fourth leading cause of cancer death and approximately half of the world’s 500,000 new ESCC cases each year occur in China[1,2]. Several studies on whole-exome sequencing (WES) in ESCC in Chinese and Japanese populations have been published recently These studies reported an extremely high frequency of TP53 mutations and low prevalence but statistically significant singlenucleotide variations (SNVs) in several other genes, including CDKN2A, NOTCH1, RB1 and PIK3CA8–15. All these WES studies only took into account somatic variations in the protein-coding regions; the protein-coding components of the genome account for only B2% of the total sequences and previous studies indicated that the non-coding regions are more frequently affected by mutations compared with the coding regions[16]. Both copy-number variations (CNVs) and structural variations (SVs) in ESCC have been reported, the results were based on lowa
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