Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

Abstract

Two major types of cancer occur in the esophagus: squamous cell carcinoma, which is associated with chronic smoking and alcohol consumption, and adenocarcinoma, which typically arises in gastric reflux-associated Barrett's esophagus. Although there is increasing incidence of esophageal adenocarcinoma in Western counties, esophageal squamous cell carcinoma (ESCC) accounts for most esophageal malignancies in East Asia, including China and Japan. Technological advances allowing for massively parallel, high-throughput next-generation sequencing (NGS) of DNA have enabled comprehensive characterization of somatic mutations in large numbers of tumor samples. Recently, several studies were published in which whole exome or whole genome sequencing was performed in ESCC tumors and compared with matched normal DNA. Mutations were validated in several genes, including in TP53 , CDKN2A , FAT1 , NOTCH1 , PIK3CA , KMT2D and NFE2L2 , which had been previously implicated in ESCC. Several new recurrent alterations have also been identified in ESCC. Combining the clinicopathological characteristics of patients with information obtained from NGS studies may lead to the development of effective diagnostic and therapeutic approaches for ESCC. As this research becomes more prominent, it is important that gastroenterologist become familiar with the various NGS technologies and the results generated using these methods. In the present study, we describe recent research approaches using NGS in ESCC.

Promoter methylation and expression of Raf kinase inhibitory protein in esophageal squamous cell carcinoma

“…Correlation between RKIP protein expression and clinicopathological characteristics. epigenetic alterations also play significant roles in the development of multiple cancers, including ESCC (30)(31)(32). Among various epigenetic alterations, aberrant DNA methylation (including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes) is the best characterized and most crucial mechanism modulating chromatin structure and the expression levels of oncogenes or tumor suppressor genes, contributing to tumor initiation and further development (33).…”

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

“…31 A couple of studies summarized and re-analyzed the genomic data from several recent genomic studies of large cohorts of ESCC patients. 32,33 The re-analysis by Du et al identified recurrent mutations in approximately 18 genes, 15 of which had been reported previously (TP53, AJUBA, CDKN2A, KMT2D (MLL2), ZNF750, FAT1, NOTCH1, NOTCH3, PIK3CA, NFE2L2, RB1, KDM6A, FBXW7, CREBBP, and TGFBR2), with three significantly mutated novel genes (CUL3, PTEN, and DCDC1). 33 Furthermore, a recent study reported 26 significantly mutated genes, including eight novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8, and BAP1) and 18 that have been previously reported.…”

“…This article also discusses the epigenetic alterations in ESCC emphasizing a major challenge of understanding epigenetic mechanisms contributing to carcinogenesis . A couple of studies summarized and re‐analyzed the genomic data from several recent genomic studies of large cohorts of ESCC patients . The re‐analysis by Du et al .…”

Impact of sequential lines of palliative chemotherapy in patients with recurrent/metastatic esophageal squamous cell carcinoma: A retrospective analysis of 107 patients at a single center

“…Studies on the molecular mechanisms involved in metastasis of ESCC gathered knowledge that it is associated with epithelial to mesenchymal transition (EMT) and EMT‐related genes and proteins . Other studies found that TP53 gene deletion, epidermal growth factor receptor (EGFR) overexpression, integrin α7, and various other mutations and proteins are associated with distant metastasis in ESCC .…”

“…Studies on the molecular mechanisms involved in metastasis of ESCC gathered knowledge that it is associated with epithelial to mesenchymal transition (EMT) and EMT-related genes and proteins. [25][26][27] Other studies found that TP53 gene deletion, epidermal growth factor receptor (EGFR) overexpression, integrin 7, and various other mutations and proteins are associated with distant metastasis in ESCC. [28][29][30] However, it is yet unknown how the level of expression of these genes and proteins differs between the initially metastatic and recurrent/progressed ESCC after curative treatment, and how they function in each disease group.…”