Dissection of gastric cancer heterogeneity for precision oncology

Abstract

Gastric cancer (GC) remains the fifth most prevalent cancer worldwide and the third leading cause of global cancer mortality. Comprehensive -omic studies have unveiled a heterogeneous GC landscape, with considerable molecular diversity both between and within tumors. Given the complex nature of GC, a long-sought goal includes effective identification of distinct patient subsets with prognostic and/or predictive outcomes to enable tailoring of specific treatments ("precision oncology"). In this review, we highlight various approaches to molecular classification in GC, covering recent genomic, transcriptomic, proteomic and epigenomic features. We pay special attention to the translational significance of classifier systems and examine potential confounding factors which deserve further investigation. In particular, we discuss recent advancements in our knowledge of intra-subtype, intra-patient and intra-tumor heterogeneity, and the pivotal role of the tumor stromal microenvironment.

Keywords: gastric cancer; molecular classification; translational research; tumor heterogeneity; tumor microenvironment.

Figure 1

Overview of current molecular classifications in gastric cancer including epigenomic, genomic, transcriptomic and proteomic alterations. Key relevant papers are referenced. CIMP, CpG island methylator phenotype; CIN, chromosomal instability; EBV, Epstein‐Barr virus; EMT, epithelial‐mesenchymal transition; G‐DIF, genomic diffuse; G‐INT, genomic intestinal; GS, genomically stable; MSI, microsatellite instability; MSS/EMT, microsatellite stable with EMT phenotype; RTK, receptor tyrosine kinase

Figure 2

Distribution of the various transcriptomic‐based (Lei et al,22 Asian Cancer Research Group [ACRG], Oh et al23) and The Cancer Genome Atlas (TCGA)‐based subtypes in two independent cohorts. A strong overlap is observed among the Lei et al mesenchymal subtype, ACRG microsatellite stable with epithelial‐mesenchymal transition phenotype (MSS/EMT) subtype and Oh et al mesenchymal phenotype subtype. TCGA genomically stable (GS) subtype is comparatively more homogenous in TCGA cohort and overlaps largely with the transcriptomic‐based mesenchymal subtypes, unlike in the ACRG cohort. CIN, chromosomal instability; EBV, Epstein‐Barr virus; MSI, microsatellite instability

Figure 3

Pervasive heterogeneity in gastric cancer between and within patients. Intra‐patient and intra‐tumoral heterogeneity exist alongside the complex tumor microenvironment. Circulating tumor DNA (ctDNA) can potentially capture heterogeneity within tumors and/or between primary and metastatic lesions. CIN, chromosomal instability; EBV, Epstein‐Barr virus; GS, genomically stable; MSI, microsatellite instability; PD‐L1, programmed death‐ligand 1