Zhao Dong-Yan, Sun Xi-Zhen, Yao Shu-Kun
Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.
World J Gastrointest Oncol. 2021 Jan 15;13(1):37-57. doi: 10.4251/wjgo.v13.i1.37.
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 , , and 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.
肿瘤突变负荷（TMB）是多种癌症中免疫治疗反应的重要独立生物标志物。然而，TMB在胃癌（GC）中的临床意义尚未完全阐明。
探索GC的突变谱格局，并确定TMB与微小RNA（miRNA）表达之间的相关性。
使用来自癌症基因组图谱的基因组、转录组和临床数据来获得突变谱，并研究突变负荷与GC患者总生存之间的统计相关性。通过Wilcoxon秩和检验评估高TMB亚组和低TMB亚组之间免疫浸润的差异。此外，鉴定高TMB亚组和低TMB亚组之间差异表达的miRNA，并采用最小绝对收缩和选择算子方法构建基于miRNA的TMB预测特征。用DIANA-miRPath v3.0鉴定预测性miRNA的生物学功能。
C>T单核苷酸突变表现出最高的突变发生率，GC中前三位突变基因是 、 和 。高TMB值（前20%）与更好的生存结果显著相关，多变量回归分析表明TMB仍然是独立于TNM分期、组织学分级、年龄和性别的预后因素。不同的TMB水平表现出不同的免疫浸润模式。在CD8+T细胞、M1巨噬细胞、调节性T细胞和CD4+T细胞的浸润方面，高TMB亚组和低TMB亚组之间观察到显著差异。此外，我们使用23个差异表达的miRNA开发了一种基于miRNA的特征来预测GC患者的TMB值。该特征的预测性能在测试集和整个数据集中得到了证实。受试者工作特征曲线分析证明了该特征的最佳性能。最后，富集分析表明，这组miRNA在许多关键的癌症和免疫相关途径中显著富集。
