PurposeImmunotherapy is regarded as the most promising treatment for cancer. However, immune checkpoint inhibitors (ICIs) are not effective for all patients. Herein, we conducted a systematic review and meta-analysis to explore whether tumor mutational burden (TMB) can be used as a potential prognostic biomarker for cancer patients treated with ICIs.MethodsWe systematically retrieved relevant literature published in the PubMed, Embase, Web of Science, and Cochrane databases up to December 28, 2020. All cohort studies and clinical trials that reported hazard ratios (HRs) for overall (OS) and progression-free survival (PFS), as well as the corresponding 95% confidence intervals (CIs) of high and low TMB patients, were included. All statistical analyses were performed using the R software.ResultsPooled results from a total of 32 studies with 6,131 participants showed significantly increased OS (HR: 0.61, 95% CI: 0.53–0.71; P <0.01) and PFS (HR: 0.51, 95% CI: 0.44–0.60; P <0.01) for the high TMB group receiving ICIs as compared to the low TMB group. Particularly, results were found to be more significant in studies with larger sample sizes (≥30), Western patients, higher TMB cutoff values (≥20 mut/Mb), anti–PD-1 therapy, and when the sample source was tissue and tumor type was either melanoma, small cell lung cancer, or gastric cancer.ConclusionTMB is a promising independent prognostic biomarker for cancer patients receiving ICIs, which could provide a new potential therapeutic strategy for high TMB patients who have failed traditional therapy. Furthermore, consistency in the key aspects of TMB assessment is expected in the future.Systematic Review Registration[https://www.crd.york.ac.uk/PROSPERO], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42021229016.
Tumor mutational burden (TMB) is considered a potential biomarker for predicting the response and effect of immune checkpoint inhibitors (ICIs). To find specific gene mutations related to TMB and the prognosis of patients, the frequently mutated genes in gastric cancer patients from TCGA and ICGC were obtained and the correlation between gene mutation, TMB, and prognosis was analyzed. Furthermore, to clarify whether specific gene mutations can be used as predictive biomarkers of ICIs, a gene set enrichment analysis (GSEA) for immune pathways and an immune infiltration analysis were conducted. The results showed that CUB and Sushi multiple domains 1 (CSMD1) mutation (CSMD1-mut) were associated with higher TMB and better prognosis in patients. The genetic map showed that, compared with wild-type samples, the loss of chromosomes 4q, 5q, 8p, and 9p decreased and the status of microsatellite instability increased in the CSMD1-mut samples. The GSEA analysis showed that immune-related pathways were enriched in the CSMD1-mut samples. The immune infiltration analysis showed that the anti-tumor immune cells were upregulated and that the tumor-promoting immune cells were downregulated in the CSMD1-mut samples. The gene co-expression analysis showed that PD-L1 expression was higher in the CSMD1-mut samples. In summary, CSMD1-mut in gastric cancer was associated with increased TMB and favorable survival and may have potential significance in predicting the efficacy of anti-PD-L1.
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