Dataset Information

Somatic mutations in ZFHX4 gene are associated with poor overall survival of Chinese esophageal squamous cell carcinoma patients.

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.

SUBMITTER: Qing T

PROVIDER: S-EPMC5504002 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Somatic mutations in ZFHX4 gene are associated with poor overall survival of Chinese esophageal squamous cell carcinoma patients.

Qing Tao T Zhu Sibo S Suo Chen C Zhang Lei L Zheng Yuanting Y Shi Leming L

Scientific reports 20170710 1

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 ...[more]

PMID: 28694483

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Project description:BackgroundIncreasing evidence shows that dysregulated long non-coding RNAs (lncRNAs) can serve as potential biomarkers for cancer prognosis. However, lncRNA signatures, as potential prognostic biomarkers for esophageal squamous cell carcinoma (ESCC), have been seldom reported.MethodsBased on our previous transcriptome RNA sequencing analysis from 15 paired ESCC tissues and adjacent normal tissues, we selected 10 lncRNAs with high score rank and characterized the expression of those lncRNAs, by qRT-PCR, in 138 ESCC and paired adjacent normal samples. These 138 patients were divided randomly into training (n = 77) and test (n = 59) groups. A prognostic signature of lncRNAs was identified in the training group and validated in the test group and in an independent cohort (n = 119). Multivariable Cox regression analysis evaluated the independence of the signature in overall survival (OS) and disease-free survival (DFS) prediction. GO and KEGG pathway analysis, combined with cell transwell and proliferation assays, are applied to explore the function of the three lncRNAs.ResultsA novel three-lncRNA signature, comprised of RP11-366H4.1.1 (ENSG00000248370), LINC00460 (ENSG00000233532) and AC093850.2 (ENSG00000230838), was identified. The signature classified patients into high-risk and low-risk groups with different overall survival (OS) and disease-free survival (DFS). For the training group, median OS: 23.1 months vs. 39.1 months, P < 0.001; median DFS: 15.2 months vs. 33.3 months, P < 0.001. For the test group, median OS: 23 months vs. 59 months, P < 0.001; median DFS: 16.4 months vs. 50.8 months, P < 0.001. For the independent cohort, median OS: 22.4 months vs. 60.4 months, P < 0.001). The signature indicates that patients in the high-risk group show poor OS and DFS, whereas patients with a low-risk group show significantly better outcome. The independence of the signature was validated by multivariable Cox regression analysis. GO and KEGG pathway analysis for 588 protein-coding genes-associated with the three lncRNAs indicated that the three lncRNAs were involved in tumorigenesis. In vitro assays further demonstrated that the three lncRNAs promoted the migration and proliferation of ESCC cells.ConclusionsThe three-lncRNA signature is a novel and potential predictor of OS and DFS for patients with ESCC.

Project description:Esophageal squamous cell carcinoma (ESCC) is one of the six most commonly diagnosed tumor types in the Chinese population. Gene expression profiles help to predict the prognosis of patients with ESCC. Disease recurrence as the survival endpoint has been analyzed in the majority of previous studies; therefore, the aim of the present study was to construct a robust gene signature in order to determine the overall survival (OS) of patients with ESCC. The gene expression and clinical data of patients with ESCC were downloaded from The Cancer Genome Atlas (TCGA) database. Of the selected data (172 samples from surviving patients), 72 samples were randomly selected as modeling data, and verification was conducted using the entire dataset. Data from the Gene Expression Omnibus was analyzed simultaneously, and a venn diagram was constructed to determine the intersection between these two sets of results; a total of 97 genes were found to be associated with OS. Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that these genes were primarily associated with specific pathways (Homo sapiens), including DNA replication, protein processing in endoplasmic reticulum and influenza A. A five-gene signature was identified with a robust likelihood-based survival modeling approach. Using regression coefficient modeling, a prognostic model consisting of the C-X-C motif chemokine ligand 8, DNA damage inducible transcript 3, RAB27A, member RAS oncogene family, replication factor C subunit 2 and elongation factor for RNA polymerase II 2 genes was constructed and validated. Based on these results, patients were subdivided into high and low-risk groups. Compared with the high-risk group, the OS time of patients in the low-risk group was significantly increased. Furthermore, it was determined that the five genes were all differentially expressed in ESCC tissues compared with normal tissues, indicating the potential role of these genes in ESCC initiation and progression. In another independent cohort, this five-gene signature was further confirmed and was considered as an independent prognostic biomarker for OS prediction in patients with ESCC. In conclusion, the OS of patients with ESCC may be predicted using this five-gene signature, which may be useful in identifying patients with high-risk ESCC.

Dataset Information

Somatic mutations in ZFHX4 gene are associated with poor overall survival of Chinese esophageal squamous cell carcinoma patients.

Publications

Somatic mutations in ZFHX4 gene are associated with poor overall survival of Chinese esophageal squamous cell carcinoma patients.

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