Published online Jan 15, 2021. doi: 10.4251/wjgo.v13.i1.37
Peer-review started: September 17, 2020
First decision: November 3, 2020
Revised: November 8, 2020
Accepted: November 28, 2020
Article in press: November 28, 2020
Published online: January 15, 2021
Tumor mutational burden (TMB) is an important independent biomarker for the response to immunotherapy in multiple cancers. However, the clinical implications of TMB in gastric cancer (GC) have not been fully elucidated.
To explore the landscape of mutation profiles and determine the correlation between TMB and microRNA (miRNA) expression in GC.
Genomic, transcriptomic, and clinical data from The Cancer Genome Atlas were used to obtain mutational profiles and investigate the statistical correlation between mutational burden and the overall survival of GC patients. The difference in immune infiltration between high- and low-TMB subgroups was evaluated by Wilcoxon rank-sum test. Furthermore, miRNAs differentially expressed between the high- and low-TMB subgroups were identified and the least absolute shrinkage and selection operator method was employed to construct a miRNA-based signature for TMB prediction. The biological functions of the predictive miRNAs were identified with DIANA-miRPath v3.0.
C>T single nucleotide mutations exhibited the highest mutation incidence, and the top three mutated genes were TTN, TP53, and MUC16 in GC. High TMB values (top 20%) were markedly correlated with better survival outcome, and multivariable regression analysis indicated that TMB remained prognostic independent of TNM stage, histological grade, age, and gender. Different TMB levels exhibited different immune infiltration patterns. Significant differences between the high- and low-TMB subgroups were observed in the infiltration of CD8+ T cells, M1 macrophages, regulatory T cells, and CD4+ T cells. In addition, we developed a miRNA-based signature using 23 differentially expressed miRNAs to predict TMB values of GC patients. The predictive performance of the signature was confirmed in the testing and the whole set. Receiver operating characteristic curve analysis demonstrated the optimal performance of the signature. Finally, enrichment analysis demonstrated that the set of miRNAs was significantly enriched in many key cancer and immune-related pathways.
Core Tip: Whether tumor mutation burden (TMB) is associated with a favorable prognosis remains controversial in various cancers. Accumulating evidence highlights that it is necessary to explore clinical impact of TMB in gastric cancer (GC). We defined the highest mutation load quintile (top 20%) in GC as the high-TMB group and found that high TMB values were associated with improved clinical outcomes, which might be attributed to the induction of antitumor immune responses in the microenvironment. We developed a microRNA-based signature to predict TMB values, which might serve as a surrogate biomarker for TMB in GC and aid physicians in clinical medical decision-making.