Abstract
Recent genome-sequencing studies have revealed dozens of genes frequently mutated in esophageal squamous cell carcinoma, but few genes are associated with patients’ clinical outcomes. Novel prognostic biomarkers are urgently needed in the clinic. We collected both somatic mutations and clinical information of 442 Chinese esophageal squamous cell carcinoma patients from four published studies. Survival analysis was performed to reveal the clinical significance of the mutated genes. Dysregulation of the mutated genes was observed from public gene-expression data sets and its effects on cell migration and invasion were investigated with siRNA-mediated silencing. Our integrated analysis revealed 26 genes significantly and frequently mutated in esophageal squamous cell carcinoma. Importantly, mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor survival. In addition, ZFHX4 was overexpressed in tumor tissues compared to normal controls, and knockdown of ZFHX4 in vitro significantly inhibited cell migration and invasion. Mutations in ZFHX4 were strongly associated with poor prognosis and the down-regulation of ZFHX4 inhibits the progression of esophageal squamous cell carcinoma. Further investigation is warranted to confirm the prognostic values of ZFHX4 in a prospective study.
Highlights
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in the world[1]
We found that mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor overall survival
The 32,493 somatic mutations were located in 12,074 human genes, including 407 genes recorded in the Catalogue of Somatic Mutations in Cancer database (COSMIC)[18]
Summary
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in the world[1]. Genome-wide association studies have identified dozens of high risk loci in ESCC, providing insights into the genetic basis of this deadly disease[6]. The aim of this study is to provide a comprehensive view of mutational profiles and identify potential prognostic biomarkers associated with clinical outcomes of ESCC. We examined somatic mutations and expression profiles of ZFHX4 in The Cancer Genome Alas (TCGA) datasets and found that the mutations of ZFHX4 were associated with poor overall survival of liver hepatocellular carcinoma patients. To the best of our knowledge, this is the first study providing direct and strong evidence regarding the role of ZFHX4 in cancer progression at both mutation and gene-expression levels. The significance of our study warrants further investigation into the potential prognostic and therapeutic utilities of ZFHX4
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