Abstract

   Esophageal cancer (EC) involves many genomic, epigenetic and
   transcriptomic disorders, which play key roles in the heterogeneous
   progression of cancer. However, the study of EC with multi-omics has
   not been conducted. This study identified a high consistency between
   DNA copy number variations and abnormal methylations in EC by analyzing
   genomics, epigenetics and transcriptomics data and investigating mutual
   correlations of DNA copy number variation, methylation and gene
   expressions, and stratified copy number variation genes (CNV-Gs) and
   methylation genes (MET-Gs). The methylation, CNVs and expression
   profiles of CNV-Gs and MET-Gs were analyzed by consistent clustering
   using iCluster integration, here, we determined three subtypes (iC1,
   iC2, iC3) with different molecular traits, prognostic characteristics
   and tumor immune microenvironment features. We also identified 4
   prognostic genes (CLDN3, FAM221A, GDF15 and YBX2) differentially
   expressed in the three subtypes, and could therefore be used as
   representative biomarkers for the three subtypes of EC. In conclusion,
   by performing comprehensive analysis on genomic, epigenetic and
   transcriptomic regulations, the current study provided new insights
   into the multilayer molecular and pathological traits of EC, and
   contributed to the precision medication for EC patients.

   Keywords: esophageal cancer, prognostic markers, copy number variation,
   methylation, multi-omics associated analysis

INTRODUCTION

   Esophageal carcinoma (EC), which is one of the most aggressive types of
   cancers, has now become the sixth leading cause of cancer-related death
   all over the world [[36]1]. The vast majority of EC take place at the
   upper and middle esophagus and are histologically classified as
   esophageal squamous cell carcinoma (ESCC), while those cases occurring
   at the lower esophagus near the stomach junction are classified as
   esophageal adenocarcinoma (EAC) [[37]2, [38]3]. China accounts for 70%
   of all EC cases, which are predominantly composed of ESCC subtypes
   [[39]2, [40]4, [41]5]. More than half of EC patients have already with
   distant metastases at diagnosis and tend to develop a 5-year survival
   of between 10% and 20% [[42]1]. Therefore, it is urgent to determine
   effective prognostic biomarkers from multiple perspectives to
   facilitate a more accurate prediction of clinical outcome and provide
   references for targeted drug development against EC.