Abstract
The genomic variant features (mutations, deletions, structural variants, etc.) within gastric cancer impact its evolution and immunogenicity. The tumor has developed several coping strategies to respond to these changes by DNA repair and replication (DRR). However, the intrinsic relationship between the associated DRR-related genes and gastric cancer progression remained unknown. This study selected DRR-related genes with tumor mutation burden based on the TCGA (The Cancer Genome Atlas) database of gastric cancer transcriptome and mutation data. The prognosis model of seven genes (LAMA2, CREB3L3, SELP, ABCC9, CYP1B1, CDH2, and GAMT) was constructed by a univariate and LASSO regression analysis and divided into high-risk and low-risk groups with the median risk score. Survival analysis showed that overall survival (OS) was lower in the high-risk group than that in the low-risk group. Moreover, patients with gastric cancer in the high-risk group have worse survival in different subgroups, including age, gender, histological grade, and TNM stage. The nomogram that included risk scores for DRR-related genes could accurately foresee OS of patients with gastric cancer. Interestingly, the tumor mutation burden score was higher in the low-risk group than that in the high-risk group, and the risk score for DRR-related genes was negatively correlated with tumor mutation burden in gastric cancer. Next, we further combined the risk score and tumor mutation burden to evaluate the prognosis of gastric cancer patients. The low-risk cohort had a better prognosis than the high-risk cohort in the high tumor mutation burden subgroup. The number of mutation types in the high-risk group was lower than that in the low-risk group. In the immune microenvironment of gastric cancer, more naïve B cells, memory resting CD4+ T cells, Treg cells, monocytes cells, and resting mast cells were infiltrated in the high-risk group. At last, PD-L1 and IAP expressions were negatively correlated with the risk scores; patients with gastric cancer in the low-risk group showed better immunotherapy outcomes than those in the high-risk group. Overall, the DRR-related gene signature based on tumor mutation burden is a novel biomarker for prognostic and immunotherapy response in patients with gastric cancer.
Highlights
Gastric cancer (GC) is one of the most common malignant tumors worldwide and the second leading cause of cancerrelated death [1, 2]
To identify a novel biomarker for prognosis and therapeutic response in GC based on DNA repair and replication (DRR)-related genes, we first screened DRR-related genes in GC based on tumor mutation burden and constructed prognostic models. en, we comprehensively evaluated the DRR-related gene signature that could predict the prognosis of GC patients and analyzed in detail the relationship between the DRR-related gene signature and the immune microenvironment in GC
Univariate Cox regression analysis screened 14 genes (MAPK10, MEOX2, LAMA2, CREB3L3, RBMS3, GHR, SELP, EFEMP1, ABCC9, APOH, INHA, CYP1B1, CDH2, and GAMT) that were associated with GC prognosis (Figure 1(d), p < 0.05)
Summary
Gastric cancer (GC) is one of the most common malignant tumors worldwide and the second leading cause of cancerrelated death [1, 2]. TMB is a quantitative biomarker that reflects the total number of mutations carried by tumor cells, and tumor cells with high TMB will have higher levels of neoantigens [8]. It is thought to assist the immune system in recognizing tumors and stimulating the proliferation of antitumor T cells [9]. Both studies reported that TMB in GC was associated with OS and clinical benefit rate, and high TMB can be used as a biomarker for the clinical efficacy of immune checkpoint blocker (ICB) in GC patients [6, 10]
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