Differences in genetics and microenvironment of lung adenocarcinoma patients with or without TP53 mutation

Abstract

Background: Differences in genetics and microenvironment of LUAD patients with or without TP53 mutation were analyzed to illustrate the role of TP53 mutation within the carcinogenesis of LUAD, which will provide new concepts for the treatment of LUAD.

Methods: In this study, we used genetics and clinical info from the TCGA database, including somatic mutations data, RNA-seq, miRNA-seq, and clinical data. More than one bioinformatics tools were used to analyze the unique genomic pattern of TP53-related LUAD.

Results: According to TP53 gene mutation status, we divided the LUAD patients into two groups, including 265 in the mutant group (MU) and 295 in the wild-type group (WT). 787 significant somatic mutations were detected between the groups, including mutations in titin (TTN), type 2 ryanodine receptor (RYR2) and CUB and Sushi multiple domains 3(CSMD3), which were up-regulated in the MU. However, no significant survival difference was observed. At the RNA level, we obtained 923 significantly differentially expressed genes; in the MU, α-defensin 5(DEFA5), pregnancy-specific glycoprotein 5(PSG5) and neuropeptide Y(NPY) were the most up-regulated genes, glucose-6-phosphatase (G6PC), alpha-fetoprotein (AFP) and carry gametocidal (GC) were the most down-regulated genes. GSVA analysis revealed 30 significant pathways. Compared with the WT, the expression of 12 pathways in the mutant group was up-regulated, most of which pointed to cell division. There were significant differences in tumor immune infiltrating cells, such as Macrophages M1, T cells CD4 memory activated, Mast cells resting, and Dendritic cells resting. In terms of immune genes, a total of 35 immune-related genes were screened, of which VGF (VGF nerve growth factor inducible) and PGC (peroxisome proliferator-activated receptor gamma coactivator) were the most significant up-regulated and down-regulated genes, respectively. Research on the expression pattern of immunomodulators found that 9 immune checkpoint molecules and 6 immune costimulatory molecules were considerably wholly different between the two groups.

Conclusions: Taking the mutant group as a reference, LUAD patients in the mutant group had significant differences in somatic mutations, mRNA-seq, miRNA-seq, immune infiltration, and immunomodulators, indicating that TP53 mutation plays a crucial role in the occurrence and development of LUAD.

Keywords: Genome; Lung adenocarcinoma; Microenvironment; Mutation; TP53.

Fig. 1

Survival analysis: survival time analysis of 501 patients with TP53 status

Fig. 2

Somatic mutation waterfall map grouped by TP53 status, the left group corresponded to the TP53 mutation group, and the right was the TP53 wild group

Fig. 3

A Volcano map of differential gene expression from TCGA database between the groups with or without TP53 mutation. (Red represents high expression in the group with TP53 mutation, blue represents high expression in the group without TP53 mutation). B Protein-protein interaction (PPI) network of differently expressed genes

Fig. 4

A Heatmap of gene set variation analysis for microarray and RNA Seq data (GSVA). B The three most significant path ways of Gene Set Enrichment Analysis (GSEA). C Barplot of significantly different pathways from KEGG analysis of all aberrant genes

Fig. 5

Immune cell infiltration landscapes in patients of LUAD with or without TP53 mutation. A Relative proportions of immune cell infiltration in the wild group and mutant group. B Correlation heat map of immune cells. C Differences in immune cell infiltration abundances between wild and mutant group

Fig. 6

Expression of immune modulators (*represents P < 0.05, ** represents P < 0.01, ***represents P < 0.001). Relative expression level of immune co-inhibitors (A) and co-stimulators (B)