Gastric cancer and genomics: review of literature

Abstract

Gastric cancer (GC) is a major health concern in many countries. GC is a heterogeneous disease stratified by histopathological differences. However, these variations are not used to determine GC management. Next-generation sequencing (NGS) technologies have become widely used, and cancer genomic analysis has recently revealed the relationships between various malignant tumors and genomic information. In 2014, studies using whole-exome sequencing (WES) and whole-genome sequencing (WGS) for GC revealed the entire structure of GC genomics. Genomics with NGS has been used to identify new therapeutic targets for GC. Moreover, personalized medicine to provide specific therapy for targets based on multiplex gene panel testing of tumor tissues has become of clinical use. Recently, immune checkpoint inhibitors (ICIs) have been used for GC treatment; however, their response rates are limited. To predict the anti-tumor effects of ICIs for GC and to select patients suitable for ICI treatment, genomics also provides informative data not only of tumors but also of tumor microenvironments, such as tumor-infiltrating lymphocytes. In therapeutic strategies for unresectable or recurrent malignant tumors, the target is not only the primary lesion but also metastatic lesions, and metastatic lesions are often resistant to chemotherapy. Unlike colorectal carcinoma, there is a heterogeneous status of genetic variants between the primary and metastatic lesions in GC. Liquid biopsy analysis is also helpful for predicting the genomic status of both primary and metastatic lesions. Genomics has become an indispensable tool for GC treatment and is expected to be further developed in the future.

Keywords: Gastric cancer; Genomics; Liquid biopsy; Next-generation sequence; Precision medicine.

Fig. 1

Genomics, epigenomics, and transcriptomics with next-generation sequencing. In genomics, the whole-exome sequence and whole-genome sequence, reading every single base of DNA systematically, can reveal copy number variations, single nucleotide variants, and gene-fusion events in the whole exome or whole genome. In epigenomics, chromatin immunoprecipitation-sequencing is used to assay the DNA fragments that bind to these transcription factors, other chromatin-associated proteins, or sites that correspond to modified nucleosomes specifically selected using antibodies. The assay for transposase-accessible chromatin using sequencing is an epigenomics technique that captures open chromatin sites using transposase, which can be inserted only in regions of open chromatin, revealing the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes, and chromatin compaction at nucleotide resolution. RNA sequencing (RNA-seq), a transcriptomics technique, can not only read every single base of RNA fragment or complementary DNA from large amounts of transcriptome data, but can also be classified into three types, including exonic reads, junction reads, and poly(A) end-reads, assemble transcriptomes with or without a reference genome, and evaluate gene expression profiling

Fig. 2

Molecular subtypes of gastric cancer classified via genomics. Gastric cancer is classified into four molecular subtypes: chromosomal instability (CIN), genome stability (GS), microsatellite instability (MSI), and Epstein-Barr virus (EBV) positivity. Most subtypes of CIN correspond to the intestinal type and are accompanied by TP53 mutations and tyrosine kinase receptor-RAS signal amplification. Most GS subtypes correspond to the diffuse type according to the histopathological classification of GC. In MSI- and EBV-positive subtypes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AT-rich interaction domain 1A (ARID1A) gene mutations are enriched. Furthermore, programmed cell death ligand 1/2 (PD-L1/2) is often overexpressed via gene amplification and structural variation in EBV-positive subgroups