RNA expression of 6 genes from metastatic mucosal gastric cancer serves as the global prognostic marker for gastric cancer with functional validation
Menée à l'aide de lignées cellulaires, d'échantillons tumoraux, de modèles murins et de l'intelligence artificielle puis validée à partir de données portant sur 519 patients atteints d'un cancer gastrique, cette étude identifie une signature, basée sur la surexpression de 4 gènes (HDAC5, NPM1, DTX3 et PPP3R1) et la perte de l'expression de 2 gènes (MED12 et TP53), pour prédire la survie
Background : Molecular analysis of advanced tumors can increase tumor heterogeneity and selection bias. We developed a robust prognostic signature for gastric cancer by comparing RNA expression between very rare early gastric cancers invading only mucosal layer (mEGCs) with lymph node metastasis (Npos) and those without metastasis (Nneg).
Methods : Out of 1003 mEGCs, all Npos were matched to Nneg using propensity scores. Machine learning approach comparing Npos and Nneg was used to develop prognostic signature. The function and robustness of prognostic signature was validated using cell lines and external datasets.
Results : Extensive machine learning with cross-validation identified the prognostic classifier consisting of four overexpressed genes (HDAC5, NPM1, DTX3, and PPP3R1) and two downregulated genes (MED12 and TP53), and enabled us to develop the risk score predicting poor prognosis. Cell lines engineered to high-risk score showed increased invasion, migration, and resistance to 5-FU and Oxaliplatin but maintained sensitivity to an HDAC inhibitor. Mouse models after tail vein injection of cell lines with high-risk score revealed increased metastasis. In three external cohorts, our risk score was identified as the independent prognostic factor for overall and recurrence-free survival.
Conclusion : The risk score from the 6-gene classifier can successfully predict the prognosis of gastric cancer.
British Journal of Cancer , article en libre accès, 2024