Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype

Abstract

Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response.

Somatic mutational profiles of stage II and III gastric cancer according to tumor microenvironment immune type

“…This genetic alteration with therapeutic implication was found exclusively within TMIT IV, in which the specific somatic mutational profile was not conspicuous. IGF2 copy number gain was observed in one TMIT II case; IGF2 acts by binding IGF1‐receptor (IGF1R) as well as IGF2‐receptor, and considering that IGF1R and its downstream signaling molecules were recently reported to have therapeutic implications in so‐called “mesenchymal phenotype (MP)” GCs, a possible relationship between TMIT II and MP subtype should be further characterized.…”

Molecular and cellular heterogeneity of gastric cancer explained by methylation-driven key regulators

“…These results are consistent with our previous observation that C3 tumors were significantly associated with invasive or mesenchymal subtype of tumors in the Singapore and Australia datasets ( Figure 4C and Supplementary Table 4). The tumors in C1 and C3 groups showed significant differences in overall survival as well as recurrence free survival (Figures 5D&E) consistently with distinct survival patterns between EP and MP groups 46 . These results suggest that the epithelial/mesenchymal phenotype can be largely explained by our methylationdriven key regulators.…”

Dissection of gastric cancer heterogeneity for precision oncology

“…Distribution of the various transcriptomic‐based (Lei et al, Asian Cancer Research Group [ ACRG ], Oh et al) 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.…”

“…A thorough understanding of the biological mechanisms underlying oncogenic alterations are likely to reveal further therapeutic opportunities, such as the synergistic effect of SHP2 and MEK2 inhibition in KRAS‐amplified GC . Previously discussed molecular classifications also hold implications for targeted therapies, exposing potential vulnerabilities such as PI3K/AKT/mTOR inhibitors in the Lei et al mesenchymal subtype, insulin‐like growth factor 1/insulin‐like growth factor 1 receptor (IGF1/IGF1R) inhibitors in the Oh et al MP subtype and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in the ACRG EMT subtype . These findings, subject to further validation, are especially exciting for the future of precision oncology, given the significant progress made recently in the development of patient‐derived organoids as drug‐testing platforms, which have shown the potential to recapitulate and predict in vivo patient clinical responses …”

“…Although the presence of CIMP in GC is well-known, its prognostic significance remains controversial. A recent meta-analysis by Powell and colleagues examined multiple cohort studies testing the association of CIMP status and overall survival in GC and F I G U R E 2 Distribution of the various transcriptomic-based (Lei et al, 22 Asian Cancer Research Group [ACRG], Oh et al 23 ) 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.…”