Integrative analysis of TP53 mutations in lung adenocarcinoma for immunotherapies and prognosis.

Background: The TP53 tumor suppressor gene is one of the most mutated genes in lung adenocarcinoma (LUAD) and plays a vital role in regulating the occurrence and progression of cancer. We aimed to elucidate the association between TP53 mutations, response to immunotherapies and the prognosis of LUAD.

Methods: Genomic, transcriptomic, and clinical data of LUAD were downloaded from The Cancer Genome Atlas (TCGA) dataset. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, gene set enrichment analysis (GSEA). Gene set variation analysis (GSVA) were performed to determine the differences in biological pathways. A merged protein-protein interaction (PPI) network was constructed and analyzed. MSIpred was used to analyze the correlation between the expression of the TP53 gene, tumor mutation burden (TMB) and tumor microsatellite instability (MSI). CIBERSORT was used to calculate the abundance of immune cells. Univariate and multivariate Cox regression analyses were used to determine the prognostic value of TP53 mutations in LUAD.

Results: TP53 was the most frequently mutated in LUAD, with a mutational frequency of 48%. GO and KEGG enrichment analysis, GSEA, and GSVA results showed a significant upregulation of several signaling pathways, including PI3K-AKT mTOR (P < 0.05), Notch (P < 0.05), E2F target (NES = 1.8, P < 0.05), and G2M checkpoint (NES = 1.7, P < 0.05). Moreover, we found a significant correlation between T cells, plasma cells, and TP53 mutations (R < 0.01, P = 0.040). Univariate and multivariate Cox regression analyses revealed that the survival prognosis of LUAD patients was related to TP53 mutations (Hazard Ratio (HR) = 0.72 [95% CI, 0.53 to 0.98], P < 0.05), cancer status (P < 0.05), and treatment outcomes (P < 0.05). Lastly, the Cox regression models showed that TP53 exhibited good power in predicting three- and five-year survival rates.

Conclusions: TP53 may be an independent predictor of response to immunotherapy in LUAD, and patients with TP53 mutations have higher immunogenicity and immune cell infiltration.