Gastric Cancer in the Era of Precision Medicine

Abstract

Gastric cancer (GC) remains the third most common cause of cancer death worldwide, with limited therapeutic strategies available. With the advent of next-generation sequencing and new preclinical model technologies, our understanding of its pathogenesis and molecular alterations continues to be revolutionized. Recently, the genomic landscape of GC has been delineated. Molecular characterization and novel therapeutic targets of each molecular subtype have been identified. At the same time, patient-derived tumor xenografts and organoids now comprise effective tools for genetic evolution studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies for GC patients. These advances are making it feasible to integrate clinical, genome-based and phenotype-based diagnostic and therapeutic methods and apply them to individual GC patients in the era of precision medicine.

Keywords: CIMP, CpG island methylator phenotype; CIN, chromosomally unstable/chromosomal instability; Cancer Genomics; EBV, Epstein-Barr virus; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; GC, gastric cancer; GTPase, guanosine triphosphatase; Gastric Cancer; HDGC, hereditary diffuse gastric cancer; LOH, loss of heterozygosity; MSI, microsatellite unstable/instability; MSI-H, high microsatellite instability; MSS/EMT, microsatellite stable with epithelial-to-mesenchymal transition features; Molecular Classification; NGS, next-generation sequencing; PDX, patient-derived tumor xenografts; Preclinical Models; TCGA, The Cancer Genome Atlas; TGF, transforming growth factor; hPSC, human pluripotent stem cell; lncRNA, long noncoding RNA; miRNA, microRNA.

Figure 1

Timeline of selected major developments in GC (above arrow) and related clinical trials (below arrow) in recent years.

Figure 2

Genetic and epigenetic characteristics of GCs.

Figure 3

Integrated precision medicine strategy for GC. Tumor specimens obtained by biopsy or circulating tumor cells are subjected to clinical-histopathologic examination and genomic analysis by NGS. Potential targetable genomic alterations are identified. Simultaneously, patient-derived tumor models (eg, xenografts or organoids) are established from the same specimens. Effective, safe therapies are then chosen by using high-throughput screening in these model systems. Finally, the patient receives optimized therapy based on this integrated strategy.