Hierarchical learning of gastric cancer molecular subtypes by integrating multi-modal DNA-level omics data and...

Molecular subtyping of gastric cancer (GC) aims to comprehend its genetic landscape. However, the efficacy of current subtyping methods is hampered by their mixed use of molecular features, a lack of strategy optimization, and the limited availability of public GC datasets. There is a pressing need for a precise and easily adoptable subtyping approach for early DNA-based screening and treatment. Based on TCGA subtypes, we developed a novel DNA-based hierarchical classifier for gastric cancer molecular subtyping (HCG), which employs gene mutations, copy number aberrations, and methylation patterns as predictors. By incorporating the closely related esophageal adenocarcinomas dataset, we expanded the TCGA GC dataset for the training and testing of HCG (n = 453). The optimization of HCG was achieved through three hierarchical strategies using Lasso-Logistic regression, evaluated by their overall the area under receiver operating characteristic curve (auROC), accuracy, F1 score, the area under precision-recall curve (auPRC) and their capability for clinical stratification using multivariate survival analysis. Subtype-specific DNA alteration biomarkers were discerned through difference tests based on HCG defined subtypes. Our HCG classifier demonstrated superior performance in terms of overall auROC (0.95), accuracy (0.88), F1 score (0.87) and auPRC (0.86), significantly improving the clinical stratification of patients (overall p-value = 0.032). Difference tests identified 25 subtype-specific DNA alterations, including a high mutation rate in the SYNE1, ITGB4, and COL22A1 genes for the MSI subtype, and hypermethylation of ALS2CL, KIAA0406, and RPRD1B genes for the EBV subtype. HCG is an accurate and robust classifier for DNA-based GC molecular subtyping with highly predictive clinical stratification performance. The training and test datasets, along with the analysis programs of HCG, are accessible on the GitHub website (github.com/LabxSCUT).