Tumor mutation burden as a biomarker in resected gastric cancer via its association with immune infiltration and hypoxia

Abstract

Background Tumor mutation burden (TMB) predicts immunotherapy efficacy in solid tumors. However, the biomarker role of TMB is still conflicting in resected tumors. We aimed to examine the association of TMB with prognosis and postoperative chemotherapy (CT) or radiochemotherapy (RCT) efficacy in resected gastric cancer (GC). Methods Whole-exome sequencing (WES) was performed in 73 resected GC specimens. Validation cohorts included 352 patients from The Cancer Genome Atlas (TCGA) and 222 patients from the Asian Cancer Research Group (ACRG). Immune infiltration and hypoxia were evaluated by transcriptome data and immunohistochemistry assay. Results TMB-high GC had favorable overall survival (OS) and disease-free survival (DFS), but the OS and DFS benefits with postoperative CT/RCT were more pronounced in TMB-low GC. These findings were consistent among all three cohorts and were maintained in the pooled cohort. Stratified by stages in the pooled cohort, stage III GC benefited from postoperative CT/RCT regardless of TMB level while stage Ib/II GC benefited from postoperative CT/RCT in TMB-low but not in TMBhigh subgroup. TMB positively correlated with immune infiltration which was characterized by NK cell rather than CD8 + T cell enrichment. TMB-high GC was more hypoxic than TMB-low GC, and TMB-high stage Ib/II GC was the most hypoxic. Conclusions High TMB may predict favorable prognosis in resected GC but poor response to postoperative CT/RCT in stage Ib/II subgroup, which may be determined by TMB-associated immune infiltration and hypoxia, respectively.

Identification of a Gene Prognostic Model of Gastric Cancer Based on Analysis of Tumor Mutation Burden

“…MUC16, which encodes the cancer antigen CA-125, was shown to be strongly associated with higher TMB and favorable survival outcomes in GC patients (30). Our result illustrated that GC patients with high TMB had a higher survival rate than those with low TMB, which was consistent with the result of Zhao et al (31), Yu et al (32) and Wang et al (33). Besides, higher TMB was associated with late T and N stages.…”

Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

“…The CHOL cohort from The Cancer Genome Atlas (TCGA) 7 and a previously reported Shanghai GBC cohort 8 were used for comparisons, and data were acquired and preprocessed as previously described. 9 Samples collection and preparation Tumor tissue and matched normal specimens were sequenced at a Clinical Laboratory Improvement Amendments-certified genomics laboratory in China. Tissue slides were first analyzed to evaluate tumor content and percentage.…”

Tumor hypoxia: an important regulator of tumor progression or a potential modulator of tumor immunogenicity?

“… 37 In one study on primary soft tissue sarcoma, the concurrent application of a hypoxia signature and a signature measuring the degree of genomic instability revealed a significant enrichment of hypoxic tumors in the group classified as having high genomic instability. 38 The positive correlation between hypoxia and TMB has been further validated in independent studies for hepatocellular carcinoma, 39 gastric cancer 40 and pancreatic cancer. 41 In gastric cancer, TMB positivity was further correlated with higher positive rate of ERO1A protein, a marker of hypoxia, in 73 tumors tested by immunohistochemistry.…”

“… 41 In gastric cancer, TMB positivity was further correlated with higher positive rate of ERO1A protein, a marker of hypoxia, in 73 tumors tested by immunohistochemistry. 40 In addition, lung adenocarcinoma patients classified as high-risk based on a signature of hypoxia-related alternative splicing events have been shown to harbor significantly higher TMB compared to the low-risk group. 42 While hypoxia could be driving TMB through its downregulation of DNA repair genes and pathways, a recent study suggests otherwise.…”

“…Furthermore, a study on gastric cancer reported TMB-high GC tumors as being positively correlated with NK cells and negatively correlated with CD8 + T-cells. 40 TMB-high tumors were also associated with the presence of hypoxia, however how the immune milieu varied between patients based on both the tumor’s mutational load and hypoxic state was not investigated. It is intriguing to think that hypoxia could instigate an increased TMB, which could give rise to immunogenic clonal neoantigens that spur immune infiltration and enhance response to ICB.…”