【Abstract】
To explore the prognosis of tumor mutation burden (TMB) and underlying relationships with tumor-infiltrating immune cells in bladder cancer (BLCA). Transcriptome profiles and somatic mutation data from The Cancer Genome Atlas database by the GDC tool. A total of 437 samples were included, consisted of 412 BLCA patients and matched 25 normal samples. Specific mutation information was summarized and illustrated in waterfall plot. Higher TMB levels revealed improved overall survival (OS) and lower tumor recurrence. We found 68 differentially expressed genes in two TMB groups and identified eight independent hub TMB-related signature. Pathway analysis suggested that differential TMB-related signature correlated with multiple cancer-related crosstalk, including cell cycle, DNA replication, cellular senescence, and p53 signaling pathway. Besides, the tumor mutation burden related signature (TMBRS) model based on eight signature possessed well predictive value with area under curve (AUC) = 0.753, and patients with higher TMBRS scores showed worse OS outcomes (p < .001). Moreover, we exhibited the inferred immune cell fractions in box plot and differential abundance of immune cells were shown in the heatmap. The Wilcoxon rank‐sum test suggested that CD8+ T cell (p=.001) and memory activated CD4+ T cell (p = .004) showed higher infiltrating levels in high‐TMB group, while the density of resting mast cells showed lower infiltrating level in high-TMB group (p = .016). Finally, it is significant to note that CD8+ T cell and memory activated CD4+ T cell subsets not only revealed higher infiltrating abundance in high-TMB group but correlated with prolonged OS and lower risk of tumor recurrence, respectively.
【中文摘要】
本研究主要探討腫瘤突變負擔（TMB）在膀胱癌中的預後價值以及與腫瘤中免疫浸潤細胞的潛在相關性。通過GDC工具從The Cancer Genome Atlas資料庫獲得轉錄組數據以及體細胞突變數據。總計包括437個樣本，其中有412名膀胱癌患者和25個正常對照樣本。通過瀑布圖概括性表明膀胱癌的突變特徵。發現較高的膀胱癌TMB水平提示較好的總體生存率（OS）和較低的腫瘤復發率（DFS）。基於此，進一步在TMB高低分組中篩選出了68個差異表達的基因，並確定了八個獨立的核心TMB相關基因簇(signature)。通路功能富集分析表明，TMB基因簇與多種癌症信號通路有關，其中包括細胞周期，DNA複製，細胞衰老和p53信號通路。此外，建立了基於八個特徵的TMB基因簇（TMBRS）模型具有良好的臨床預測價值，其曲線下面積（AUC）達到0.753，且TMBRS得分較高的患者顯示較差的OS結局（p <.001）。此外，通過CIBERSORT算法中計算了TMB兩組中重要的免疫細胞組分，以及浸潤的差異豐度。Wilcoxon秩和檢驗表明，高TMB組的CD8 + T細胞（p = .001）和記憶激活的CD4 + T細胞（p = .004）表現出較高的浸潤水平，而靜息型肥大細胞在高TMB組中則顯示較低的浸潤水平（p = .016）。最後，值得注意的是，高TMB組的CD8 + T細胞和記憶激活型CD4 + T細胞亞群不僅顯示較高的浸潤豐度，而且分別與延長的OS和較低的腫瘤復發風險相關。