Combination of Tumor Mutational Burden and DNA Damage Repair Gene Mutations with Stromal/Immune Scores Improved Prognosis Stratification in Patients with Lung Adenocarcinoma

BACKGROUND: Both the tumor environment and the genomic landscape of lung cancer may shape patient responses to treatments, including immunotherapy, but their joint impacts on lung adenocarcinoma (LUAD) prognosis are underexplored. METHODS: RNA sequencing data and whole-exome sequencing results were downloaded from the TCGA database, and only LUAD-related data were included in this study. Based on gene expression data, the ESTIMATE algorithm was used to estimate stromal and immune scores, and CIBERSORT analysis was used for quantification of the relative abundances of immune cells. Somatic mutations were used for calculating tumor mutation burden (TMB). Specific mutations in genes involved in DNA damage repair (DDR) pathways were identified. The individual and joint associations of stromal and immune score, TMB, and DDR gene mutations with 5-year survival were analyzed by the Kaplan–Meier method and multivariate Cox model. RESULTS: LUAD patients with a high (>highest 25%) stromal or immune score had prolonged survival as compared to those with a low (<lowest 25%) score (log-rank P=0.05 and 0.035, respectively). Patients with both high stromal and immune scores had the most favorable survival. Although the survival differences between patients with high (>highest 25%) and low (<lowest 25%) TMB, or between patients with mutant- and wild-type DDR genes were not statistically significant, a survival benefit from high TMB or DDR gene mutations was observed in patients with high stromal or immune scores. CONCLUSION: A comprehensive evaluation of transcriptomic signatures and genomic biomarkers may provide a novel avenue for improving prognosis stratification in LUAD.