Abstract

BackgroundDNA methylation has been implicated as a promising biomarker for precise cancer diagnosis. However, limited DNA methylation-based biomarkers have been described in esophageal squamous cell carcinoma (ESCC).MethodsA high-throughput DNA methylation dataset (100 samples) of ESCC from The Cancer Genome Atlas (TCGA) project was analyzed and validated along with another independent dataset (12 samples) from the Gene Expression Omnibus (GEO) database. The methylation status of peripheral blood mononuclear cells and peripheral blood leukocytes from healthy controls was also utilized for biomarker selection. The candidate CpG sites as well as their adjacent regions were further validated in 94 pairs of ESCC tumor and adjacent normal tissues from the Chinese Han population using the targeted bisulfite sequencing method. Logistic regression and several machine learning methods were applied for evaluation of the diagnostic ability of our panel.ResultsIn the discovery stage, five hyper-methylated CpG sites were selected as candidate biomarkers for further analysis as shown below: cg15830431, P = 2.20 × 10−4; cg19396867, P = 3.60 × 10−4; cg20655070, P = 3.60 × 10−4; cg26671652, P = 5.77 × 10−4; and cg27062795, P = 3.60 × 10−4. In the validation stage, the methylation status of both the five CpG sites and their adjacent genomic regions were tested. The diagnostic model based on the combination of these five genomic regions yielded a robust performance (sensitivity = 0.75, specificity = 0.88, AUC = 0.85). Eight statistical models along with five-fold cross-validation were further applied, in which the SVM model reached the best accuracy in both training and test dataset (accuracy = 0.82 and 0.80, respectively). In addition, subgroup analyses revealed a significant difference in diagnostic performance between the alcohol use and non-alcohol use subgroups.ConclusionsMethylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) can be used for effective methylation-based testing for ESCC diagnosis.

Highlights

  • DNA methylation has been implicated as a promising biomarker for precise cancer diagnosis

  • The incidence of esophageal adenocarcinoma (EAC) is higher in Western countries, while the esophageal squamous cell carcinoma (ESCC) subtype is predominant in Asians, especially in China (88.84%), suggesting that the studies of ESCC in the Chinese population is of great importance [6,7,8,9,10]

  • The esophageal carcinoma methylation dataset from The Cancer Genome Atlas (TCGA) was first identified, with 84 ESCC tumors and 3 ESCC adjacent normal tissue samples, as well as 78 EAC tumors and 13 EAC adjacent normal tissues

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Summary

Introduction

DNA methylation has been implicated as a promising biomarker for precise cancer diagnosis. Limited DNA methylation-based biomarkers have been described in esophageal squamous cell carcinoma (ESCC). DNA methylation alterations have been found to occur early in the carcinogenesis and could be applied as a promising biomarker for cancer early detection [20,21,22]. Despite of several diagnostic panels for ESCC detection, these studies were limited by the relatively small sample size, inaccurate methylation detection methods, and lack of validation datasets. Biomarkers with these limitations may pose a burden for the further prospective studies with large sample sizes

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