An updated review of gastric cancer in the next-generation sequencing era: Insights from bench to bedside and vice versa

Abstract

Gastric cancer (GC) is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs. Recent studies using next-generation sequencing (NGS) have revealed a number of potential cancer-driving genes in GC. Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4, a member of the cadherin gene family. Mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) have been found in 47% of GCs. Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC. Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery, such as DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs and microRNAs. Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings. The anti-human epidermal growth receptor 2 (HER2) antibody trastuzumab has led to an era of personalized therapy in GC. In addition, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor (VEGFR)-2, is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after first-line chemotherapy. Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets, as well as useful biomarkers. In this review, we will summarize the recent advances in the understanding of the molecular pathogenesis of GC, focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.

Keywords: Next-generation sequencing, Microsatellite instability, MicroRNA, Epigenetic field defect, Gastric washes, Insulin-like growth factor 1 receptor

Core tip: The genetic and epigenetic alterations in gastric cancers (GC) have biological and clinical implications. Recent advances in the molecular research of GC have introduced new diagnostic and therapeutic strategies to clinical settings. In this review, we summarize the key findings of past reports pertaining to the genetics and epigenetics of GC and their relationship to and future applications in next-generation sequencing (NGS). We also describe the recurrently mutated genes and alterations in GC identified by NGS technology and discuss the basic framework for future investigations, including the challenges of using NGS as a tool for biomarker and therapeutic target discovery.