Development and Validation of a Novel Signature to Predict Overall Survival in “Driver Gene–negative” Lung Adenocarcinoma (LUAD): Results of a Multicenter Study

Purpose: Examining the role of developmental signaling pathways in "driver-gene-negative" LUAD (LUAD patients negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET and ROS1 were identified as "driver-gene-negative") may shed light on the clinical research and treatment for this LUAD subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of "driver-gene-negative" LUAD. Experimental Design: In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired LUAD and adjacent normal tissues. In the training phase, tissue microarrays (TMAs) and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature. Results: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in "driver-gene-negative" LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/β-catenin-pathway-based CSDW signature comprising 4 genes (CTNNB1 or β-catenin, SOX9, DVL3 and Wnt2b) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10.42, 6.46-16.79; p