Tumor Nonimmune-Microenvironment-Related Gene Expression Signature Predicts Brain Metastasis in Lung Adenocarcinoma Patients after Surgery: A Machine Learning Approach Using Gene Expression Profiling

Abstract

Using a machine learning approach with a gene expression profile, we discovered a tumor nonimmune-microenvironment-related gene expression signature, including extracellular matrix (ECM) remodeling, epithelial–mesenchymal transition (EMT), and angiogenesis, that could predict brain metastasis (BM) after the surgical resection of 64 lung adenocarcinomas (LUAD). Gene expression profiling identified a tumor nonimmune-microenvironment-related 17-gene expression signature that significantly correlated with BM. Of the 17 genes, 11 were ECM-remodeling-related genes. The 17-gene expression signature showed high BM predictive power in four machine learning classifiers (areas under the receiver operating characteristic curve = 0.845 for naïve Bayes, 0.849 for support vector machine, 0.858 for random forest, and 0.839 for neural network). Subgroup analysis revealed that the BM predictive power of the 17-gene signature was higher in the early-stage LUAD than in the late-stage LUAD. Pathway enrichment analysis showed that the upregulated differentially expressed genes were mainly enriched in the ECM–receptor interaction pathway. The immunohistochemical expression of the top three genes of the 17-gene expression signature yielded similar results to NanoString tests. The tumor nonimmune-microenvironment-related gene expression signatures found in this study are important biological markers that can predict BM and provide patient-specific treatment options.