DNA Repair-Based Gene Expression Signature and Distinct Molecular Subtypes for Prediction of Clinical Outcomes in Lung Adenocarcinoma

Objective: To conduct a robust prognostic gene expression signature and characterize molecular subtypes with distinct clinical characteristics for lung adenocarcinoma (LUAD). Methods: Based on DNA repair genes from the GSEA database, a prognostic signature was conducted in the TCGA-LUAD training set via univariate and multivariate cox regression analysis. Its prediction power was validated by overall survival analysis, relative operating characteristic (ROC) curves and stratification analysis in the GSE72094 verification set. Involved pathways in the high- and low-risk groups were analyzed by GSEA. A nomogram was built based on the signature and clinical features and its performance was assessed by calibration plots. LUAD samples were clustered via the ConsensusClusterPlus package. The differences in clinical outcomes, single nucleotide polymorphism (SNP) and sensitivity to chemotherapy drugs between molecular subtypes were analyzed. Results: A 13-DNA repair gene-signature was constructed for LUAD prognosis. Following validation, it can robustly and independently predict patients' clinical outcomes. The GSEA results exhibited the differences in pathways between high- and low- risk groups. A nomogram combining the signature and stage could accurately predict 1-, 3-, and 5-year survival probability. Two distinct molecular subtypes were characterized based on DNA repair genes. Patients in the Cluster 2 exhibited a worse prognosis and were more sensitive to common chemotherapy than those in the Cluster 1. Conclusion:This study proposed a 13-DNA repair gene-signature as a prognostic factor for LUAD patients, which can independently predict clinical outcomes by complement of the stage. Moreover, we characterized two LUAD subtypes with distinct clinical outcomes, somatic gene mutations, and drug sensitivity in cancer based on DNA repair genes.