Abstract
The early diagnosis and accurate prognosis prediction of esophageal cancer is an essential part of improving survival. However, these diseases lack effective and specific markers. A total of 1,744 samples of HumanMethylation450 data were integrated to identify and validate specific methylation markers for esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) as well as for Barrett’s esophagus (BE) using The Cancer Genome Atlas and the Gene Expression Omnibus. The diagnostic and prognostic methylation classifiers were constructed by moderated t-statistics and the least absolute shrinkage and selection operator method. The diagnostic methylation classifier using 12 CpG sites was constructed in training set (377 samples) that could effectively discriminate samples of BE, EAC, and ESCC from normal tissue (AUC = 0.992), which achieved highly predictive ability in both internal (187 samples, AUC = 0.990) and external validation (184 samples, AUC = 0.978). The prognostic methylation classifier with 3 CpG and 2 CpG sites for EAC and ESCC respectively, could accurately estimate the prognosis of an individual patient and improved the predictive ability of the tumor node metastasis staging system. Overall, our study systematically analyzed large-scale methylation data and provided promising markers for the diagnosis and prognosis of esophageal cancer.
Highlights
Esophageal cancer is the seventh most common cancer and the sixth leading cause of cancer death in the world [1]
Esophageal cancer is subdivided into two histologic types, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), of which 88% of the cases are ESCC
After feature selection by the least absolute shrinkage and selection operator (LASSO) model using 10 times random partitions and 10-fold cross-validation, we identified 458 CpG sites with different frequencies (Supplementary Figure 3)
Summary
Esophageal cancer is the seventh most common cancer and the sixth leading cause of cancer death in the world [1]. Esophageal cancer is subdivided into two histologic types, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), of which 88% of the cases are ESCC. The risk factors and molecular characteristics of ESCC and EAC are different [2]. Genome sequencing studies have revealed that two histologic types of esophageal cancers exhibit distinct molecular profile at both genomic and epigenomic levels [6,7,8]. Genetic makers, such as somatic mutations, may be below the detection limit due to a low tumor load in early stages of cancer, and represent multiple cancer types and non-tumor conditions [9, 10]. Typespecific epigenomic markers for diagnosis and prognosis of esophageal cancer have not been systematically compared and identified
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