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Genetic polymorphisms of ATG5 predict survival and recurrence in patients with early-stage esophageal squamous cell carcinoma.

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is a deadly disease with high risk of tumor recurrence even among patients with an early pathologic stage of tumor. In the current study, we investigate the association between 20 SNPs of the ATG5 gene and prognosis of patients with early-stage ESCC. A total of 305 patients diagnosed with early-stage ESCC were enrolled in the study and randomly assigned to a training set (n=93) or replication set (n=212). The genotypes of candidate SNPs (single nucleotide polymorphisms) within ATG5 were analyzed and correlated with the prognosis of ESCC patients. We repeatedly demonstrated that 3 SNPs in ATG5, rs1322178, rs3804329, and rs671116, were significantly correlated with the prognosis of patients with early-stage ESCC (HR[95 % CI]=2.01[1.19-3.40], p=0.009 for ATG5: rs1322178; HR[95 % CI]=1.88 [1.08-3.26], p=0.025 for ATG5:rs3804329; HR[95 % CI]=1.73[1.24-2.42], p=0.001 for ATG5:rs671116, in combined group). Both rs1322178 and rs3804329 can predict early distant metastasis of patients. Furthermore, increased expression of ATG5 was observed in ESCC tumor tissue as compared to adjacent normal tissue. Moreover, higher levels of ATG5 expression in both normal and tumor tissues exhibited a trend to correlate with poor prognosis of patients. However, the expression of ATG5 did not correlate with these 3 relevant prognostic SNPs. We concluded that hereditary genetic polymorphisms and gene expression of ATG5 can serve as prognostic predictors of patients with early-stage ESCC.

SUBMITTER: Yang PW

PROVIDER: S-EPMC5710940 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Genetic polymorphisms of ATG5 predict survival and recurrence in patients with early-stage esophageal squamous cell carcinoma.

Yang Pei-Wen PW Hsieh Min-Shu MS Chang Ya-Han YH Huang Pei-Ming PM Lee Jang-Ming JM

Oncotarget 20170908 53

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with high risk of tumor recurrence even among patients with an early pathologic stage of tumor. In the current study, we investigate the association between 20 SNPs of the ATG5 gene and prognosis of patients with early-stage ESCC. A total of 305 patients diagnosed with early-stage ESCC were enrolled in the study and randomly assigned to a training set (n=93) or replication set (n=212). The genotypes of candidate SNPs (single nucleotid ...[more]

PMID: 29207660

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Project description:ObjectiveOur previous study suggested cyclin-dependent kinase-like 3 (CDKL3) acts as a new oncogene in esophageal squamous cell carcinoma (ESCC) cell line TE-1. However, the molecular mechanisms and biological effects of CDKL3 in ESCC remain unknown. In the present study, we aimed to explore the clinical significance of CDKL3 in ESCC and how CDKL3 regulates the malignant behavior of ESCC.MethodsESCC samples were stained by immunohistochemical staining (IHC) and analyzed for the expression of CDKL3. The functions of CDKL3 on proliferation, apoptosis, migration, invasion, and colony formation were investigated by celigo assay, MTT assay, colony formation, caspase 3/7 activity analysis, transwell migration and invasion assay, respectively. A transplanted tumor model was established to study the functions of FLVCR1 on the tumorigenesis of ESCC cells. Microarray analysis was utilized to identify the CDKL3-regulated genes in ESCC cells.ResultsESCC tumor tissues possessed a significantly higher expression of CDKL3 and autophagy-related gene 5 (ATG5) than matched adjacent normal tissues. The high expressions of CDKL3 were positively associated with the tumor-node-metastasis (TNM) stage and Ki67. Upregulated ATG5 expression was positively correlated with male, advanced tumor (T) stage, and TNM stage. Kaplan-Meier analysis showed that ESCC patients with higher expression of CDKL3 or ATG5 had a shorter overall survival. The worst prognosis was recognized in patients with both high manifestations of CDKL3 and ATG5. Time-dependent receiver operating characteristic (ROC) curve was established to reveal that the combination of CDKL3, ATG5, and TNM stage-based model had better prognostic accuracy than TNM stage. Moreover, CDKL3 knockdown markedly repressed cell growth and aggressivity in vitro and in vivo. Mechanistically, ATG5 was confirmed as a downstream gene involved in the pro-oncogenic function of CDKL3.ConclusionCDKL3 can be utilized as an independent poor prognostic marker in ESCC patients. Furthermore, CDKL3 may promote tumor profession, invasion, metastasis, and prohibit tumor apoptosis partly by ATG5 activation.

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

Genetic polymorphisms of ATG5 predict survival and recurrence in patients with early-stage esophageal squamous cell carcinoma.

Publications

Genetic polymorphisms of ATG5 predict survival and recurrence in patients with early-stage esophageal squamous cell carcinoma.

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