Identification of New Therapeutic Targets for Gastric Cancer With Bioinformatics

Abstract

We aimed to identify new targets affecting gastric cancer (GC) prognosis. Six target genes were identified from hub genes based on their relationship with important factors affecting tumor progression, like immune infiltration, purity, tumor mutation burden (TMB), and tumor microenvironment (TME) score. The effect of target genes' somatic mutations and copy number alteration (CNA) was examined to determine their effect on GC prognosis. Six target genes (FBN1, FN1, HGF, MMP9, THBS1, and VCAN) were identified. Reduced expression of each target gene, except MMP9, indicated better prognosis and lower grade in GC. FBN1, THBS1, and VCAN showed lower expression in stage I GC. Non-silencing mutations of the six genes played a role in significantly higher TMB and TME scores. THBS1 mutation was associated with earlier stage GC, and VCAN mutation was associated with lower grade GC. However, patients with target gene CNA displayed higher tumor purity. MMP9, THBS1, and VCAN CNA was associated with lower grade GC, while FBN1 CNA reflected earlier T stage. Additionally, the target genes may affect GC prognosis by influencing multiple oncogenic signaling pathways. FBN1, FN1, HGF, MMP9, THBS1, and VCAN may be new GC prognostic targets by affecting tumor purity, TMB, TME score, and multiple oncogenic signaling pathways.

Keywords: CNA; TMB; TME score; gastric cancer; mutation; prognosis; purity.

FIGURE 1

The analysis chart of our study.

FIGURE 2

Heat maps and GO-BP of differential gene expression analysis in sensitized and drug-resistant cells. (A) Heat map of the genes differentially expressed between 5FU-sensitive and non-sensitive cells, (B) heat map of differentially expressed genes in Oxaliplatin groups, (C) GO analysis of downregulated genes revealed that these genes were primarily involved in the negative regulation of endopeptidase activity, cell adhesion, inflammatory response, extracellular matrix organization, etc., (D) upregulated genes were primarily involved in positive and negative regulation of transcription from RNA polymerase II promoter, negative regulation of apoptosis, chemical synaptic transmission, etc.

FIGURE 3

Expression of 30 hub genes in TCGA-STAD and normal tissue from GTEx dataset. *P < 0.05.

FIGURE 4

Correlation between hub genes and immune infiltration. (A) Correlation between MMP9 and macrophages (M0), IL1B and neutrophils, and IL1B and activated mast cells, (B) correlation between the expression of the 30 hub genes and 22 types of immune cells. **P < 0.01; *P < 0.05.

FIGURE 5

Correlation between hub genes expression and important factors. (A) Heat map of the hub genes expression according to the TME score and tumor purity, (B) correlation between hub gene expression and TMB, TME score, tumor purity, immune score, and stromal score.

FIGURE 6

Mutation of target genes and the effect on purity, TMB and TME score. (A) Six hub gene mutation frequency in TCGA-STAD, (B) comparison of mRNA expression, tumor purity, immune score, stromal score, log2TMB, and TME score between the mutated and wild type group. ***P < 0.005; *P < 0.05.

FIGURE 7

CNA of target genes and the effect on purity, TMB, and TME score. (A) Number of mutations and CNA for the 30 hub genes, (B) expression of the six target genes in the CNA and non-CNA group, (C) expression of the six target genes in different CNA subtype group. ***P < 0.005; **P < 0.01; *P < 0.05.

FIGURE 8

Comparison of purity, TMB, and TME score among different CNA subtype. (A) Tumor purity in different target gene CNA types, (B) immune score in different target gene CNA types, (C) stromal score in different target gene CNA types, (D) log2TMB in different target gene CNA types, (E) TME score in different target gene CNA types. ***P < 0.005; **P < 0.01; *P < 0.05.

FIGURE 9

Expression of target genes and clinical characteristics. (A) Relationship between target genes and clinical stage, (B) relationship between target genes and clinical grade, (C) univariate cox analysis and Kaplan-Meier (KM) of target genes. ***P < 0.005; **P < 0.01; *P < 0.05.

FIGURE 10

KM of target genes with mutation or CNA. (A) KM survival between the CNA and non-CNA group of target genes, (B) KM survival between the mutated and wild type group of target genes.

FIGURE 11

Alteration ratio of 10 signaling pathway in mutation and CNA groups. (A) Number of changes in each pathway for the mutated and wild type groups of target genes, (B) percentage of change numbers in each pathway for the mutated and wild type groups of target genes, (C) number of changes in each pathway for the CNA and non-CNA groups of target genes, (D) percentage of change numbers in each pathway for the CNA and non-CNA groups of target genes. ***P < 0.005; **P < 0.01; *P < 0.05.

FIGURE 12

Co-occurrence and mutual exclusivity between target genes and key genes in each pathway. Green indicates co-occurrence and purple indicates mutual exclusivity; ***P < 0.005; **P < 0.01; *P < 0.05.