Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations

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.

A functional variant in TNXB promoter associates with the risk of esophageal squamous‐cell carcinoma

“…We used data from three sources to analyze the differential expression of TNXB between tumor and adjacent normal tissues. RNA‐seq data for 94 ESCC tissues were derived from our previous study 28 . In addition, two RNA‐seq datasets of ESCC were downloaded from Gene Expression Omnibus (GEO) database with GEO accession numbers being GSE20347 29 and GSE23400 30 .…”

“…We extracted messenger RNA (mRNA) expression data for all genes in ESCC tumor samples from the TCGA database and our previous study 28 to quantify the co‐expression relationship of each gene with TNXB . Genes with a P value of less than .05 were grouped into positive co‐expression and negative co‐expression according to their Spearman correlation coefficients (>0.3 or <–0.3).…”

“…RNA-seq data for 94 ESCC tissues were derived from our previous study. 28 In addition, two RNA-seq datasets of ESCC were downloaded from Gene Expression Omnibus (GEO) database with GEO accession numbers being GSE20347 29 and GSE23400 30 . Gene expression results of multiple types of cancer from TCGA was downloaded using the R package RTCGAToolbox.…”

Metabolic remodeling by TIGAR overexpression is a therapeutic target in esophageal squamous-cell carcinoma

“…We previously identified 23 focal amplified regions overlapping 1,591 genes (Chang et al, 2017). Of them, 149 genes were significantly overexpressed in tumor samples (differential expression analysis P<0.05, fold change >1.35) and their expression levels were significantly correlated with their copy-number gains (Spearman’s correlation coefficient >0.35, P<0.05).…”

“…In recent years, high-throughput genome-wide screening for amplified and overexpressed genes has accelerated the discovery of potential molecular targets for drug development (Guichard et al, 2012; Santarius et al, 2010). In our previous whole-genome sequencing (WGS) study on 94 ESCC samples, we identified 23 focal recurrent copy number gain regions containing 1,591 genes and the matched mRNA expression data showed 149 copy-number gain genes were overexpressed in tumor compared with adjacent normal samples (Chang et al, 2017). These results are consistent with the TCGA ESCC data, indicating that ESCC is a type of cancer dominated by CNVs (Beroukhim et al, 2010).…”