Detection of Potential Mutated Genes Associated with Common Immunotherapy Biomarkers in Non-Small-Cell Lung Cancer Patients

Abstract

Microsatellite instability (MSI), high tumor mutation burden (TMB-H) and programmed cell death 1 ligand 1 (PD-L1) expression are hot biomarkers related to the improvement of immunotherapy response. Two cohorts of non-small-cell lung cancer (NSCLC) were collected and sequenced via targeted next-generation sequencing. Drug analysis was then performed on the shared genes using three different databases: Drugbank, DEPO and DRUGSURV. A total of 27 common genes were mutated in at least two groups of TMB-H-, MSI- and PD-L1-positive groups. AKT1, SMAD4, SCRIB and AXIN2 were severally involved in PI3K-activated, transforming growth factor beta (TGF-β)-activated, Hippo-repressed and Wnt-repressed pathways. This study provides an understanding of the mutated genes related to the immunotherapy biomarkers of NSCLC.

Keywords: gene mutation; immunotherapy; microsatellite instability; non-small-cell lung cancer; programmed cell death protein-1; tumor mutation burden.

Figure 1

The shared mutated genes between TMB-H, MSI and PD-L1-positive groups. (A) Venn diagram of unique mutated gene from TMB-H, MSI and PD-L1-positive groups. There were 27 common genes in the three groups, and these genes appeared in at least two groups. (B) Heatmap showing the mutation frequency and percentage of 27 common genes in different groups. These genes had different mutation frequencies and percentages among these patients.

Figure 1

The shared mutated genes between TMB-H, MSI and PD-L1-positive groups. (A) Venn diagram of unique mutated gene from TMB-H, MSI and PD-L1-positive groups. There were 27 common genes in the three groups, and these genes appeared in at least two groups. (B) Heatmap showing the mutation frequency and percentage of 27 common genes in different groups. These genes had different mutation frequencies and percentages among these patients.

Figure 2

The functional enrichment analysis. (A) The most significant GO terms of the 27 common genes. Many studies have indicated that the great majority of GO terms are related to cancer development. (B) The most significant pathways of the 27 common genes. All of these pathways play a role in cancer.

Figure 2

The functional enrichment analysis. (A) The most significant GO terms of the 27 common genes. Many studies have indicated that the great majority of GO terms are related to cancer development. (B) The most significant pathways of the 27 common genes. All of these pathways play a role in cancer.

Figure 3

Types and functions of characteristics of immune cells in different groups. (A) Heatmap depicting immune cell type and function of all mutated genes in group 1. There were 25 kinds of immune cell type and function among these genes that were mutated in group 1. (B) Heatmap showing types and functions of immune cells of all mutated genes in group 2. These mutated genes were enriched in 26 categories of immune cell types and functions. (C) The number of people with the mutation genes related to immune cell type and function were compared between TMB-L and TMB-H, and there were 2 kinds of differential immune cell type and function between TMB-L and TMB-H groups.

Figure 4

Analysis of immune-related pathway. (A) Heatmap depicting immune-related pathway of all mutated genes in group 1. There were 15 kinds of immune-related pathway among these genes that were mutated in group 1. (B) Heatmap showing immune-related pathway of all mutated genes in group 2. These mutated genes were involved in 17 categories of immune-related pathway.

Figure 5

Analysis of differences in immune-related pathway. (A) The difference in the number of people with all the mutation genes related to RAS-activated, TGFB-activated, TP53-activated and Wnt-repressed pathway between TMB-L and TMB-H groups. (B) The difference in the number of people with 27 common genes related to Wnt-repressed pathway between TMB-L and TMB-H groups and MSI and MSS groups.

Figure 6

Drug analysis of 27 shared genes. (A) Drugs related to 27 common genes in the DEPO drug database. A total of 5 genes among these 27 common genes had related drugs. (B) Drugs related to 27 common genes in DRUGSURV drug database. A total of 18 genes had drugs that were directly or indirectly related.