Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype

Nat Commun. 2018 May 3;9(1):1777. doi: 10.1038/s41467-018-04179-8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Chemotherapy, Adjuvant
  • Drug Resistance, Neoplasm
  • Epithelial-Mesenchymal Transition
  • Female
  • Gastrointestinal Stromal Tumors / drug therapy
  • Gastrointestinal Stromal Tumors / genetics*
  • Gastrointestinal Stromal Tumors / metabolism
  • Gastrointestinal Stromal Tumors / pathology*
  • Gene Expression Regulation, Neoplastic*
  • Heterografts
  • Humans
  • Kaplan-Meier Estimate
  • Mesoderm / pathology*
  • Mice, Inbred BALB C
  • Microsatellite Instability
  • Mutation
  • Prognosis
  • Proteomics
  • Receptor, IGF Type 1 / metabolism
  • Reproducibility of Results
  • Signal Transduction
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*


  • Antineoplastic Agents
  • Receptor, IGF Type 1