Molecular Characterization of Gastric Cancer Subtypes

Gastric cancer represents a heterogeneous group of tumours with distinct histological and molecular features that underpin variations in prognosis and therapeutic response. Contemporary classification schemes, notably those proposed by The Cancer Genome Atlas and the Asian Cancer Research Group, define four principal molecular subtypes: Epstein–Barr virus-positive, microsatellite instability-high, chromosomal instability and genomically stable. Each subtype is characterised by specific genomic alterations—such as PIK3CA mutations in Epstein–Barr virus-positive tumours, mismatch-repair defects underpinning microsatellite instability and TP53 mutations with frequent receptor tyrosine kinase amplification in the chromosomal instability group. The genomically stable subtype, often associated with diffuse histology, exhibits mutations in cell-adhesion genes such as CDH1 and alterations in RHOA signalling. Advances in high-throughput proteomics, phosphoproteomics and transcriptional profiling have refined this taxonomy, identifying proteomic and immune-related signatures that further subdivide diffuse-type and intestinal-type gastric cancers. Integrative analyses have revealed dysregulated cell-cycle pathways, extracellular matrix remodelling and distinct immune infiltration patterns that correlate with clinical outcomes and guide precision medicine strategies, including targeted therapies and immunotherapy. Ongoing efforts aim to incorporate epigenomic and metabolomic data to furnish a holistic molecular map capable of informing patient stratification and novel therapeutic development.

Research from Nature Portfolio

Recent studies have applied multilevel proteomic analyses to compare diffuse-type and intestinal-type gastric cancers. Comprehensive proteome, phosphoproteome and transcription factor activity profiling across a large patient cohort uncovered ARID1A mutation as a context-dependent prognostic biomarker, influencing cell-cycle regulation, extracellular matrix organisation and immune response. Consensus clustering delineated three subgroups within each histological type, each associated with unique signalling pathways and differential sensitivity to immunotherapy, as reflected by Th1/Th2 ratios. Earlier work established a proteomic landscape of diffuse-type gastric cancer, classifying tumours into three proteome-defined subtypes (PX1–3). PX3, characterised by heightened immune response signatures, demonstrated the poorest survival and resistance to chemotherapy, while proteomic vulnerabilities suggested candidate targets for immunotherapeutic intervention. Together, these proteogenomic efforts provide a refined molecular framework for subtype-specific treatment approaches and prognostic assessment.

Molecular Characterization of Gastric Cancer Subtypes publication trend

The graph below shows the total number of articles in molecular characterization of gastric cancer subtypes across all publications each year (not limited to Nature Index journals).

Technical terms

Proteogenomic analysis: Integration of protein expression and genomic alteration data to characterise tumour biology.

Phosphoproteome: The complete set of phosphorylated proteins within a cell or tissue, reflecting signalling pathway activity.

Transcription factor activity: A measure of regulatory proteins’ influence on gene expression programmes.

ARID1A mutation: Alteration in a chromatin remodelling gene that modulates DNA accessibility and transcription.

CDH1 mutation: Loss or alteration of the E-cadherin gene, leading to impaired cell adhesion and increased invasiveness.

Microsatellite instability (MSI): A condition of genetic hypermutability resulting from impaired DNA mismatch repair, marked by variation in short tandem repeats.

References

1. Multilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer. Nature Communications (2023).
2. Large-scale analysis of CDH1 mutations defines a distinctive molecular subset with treatment implications in gastric cancer. npj Precision Oncology (2024).
3. RNA expression of 6 genes from metastatic mucosal gastric cancer serves as the global prognostic marker for gastric cancer with functional validation. British Journal of Cancer (2024).
4. Molecular Classifications in Gastric Cancer: A Call for Interdisciplinary Collaboration. International Journal of Molecular Sciences (2024).
5. A proteomic landscape of diffuse-type gastric cancer. Nature Communications (2018).