Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
Curr Probl Cancer. 2021 Apr;45(2):100660. doi: 10.1016/j.currproblcancer.2020.100660. Epub 2020 Sep 29.
To explore the prognostic value of tumor mutation burden (TMB) and its correlation with immune infiltrates in endometrial cancer. Transcriptome and somatic mutation profiles of Uterine Corpus Endometrial Carcinoma (UCEC) were downloaded from TCGA database. Somatic mutations were analyzed by "maftools" and visualized in waterfall plot. We calculated TMB of each patients and divided all patients into the high-TMB group and the low-TMB group by the median threshold. Survival analysis and Wilcoxon test were used to investigate the prognostic value of TMB and its association with clinical variables. Differentially expressed genes (DEGs) were identified in 2 TMN groups and functional analysis was performed to find out significant biological pathways. A TMB-related signature was conducted by multivariate analysis, receiver operating characteristic (ROC) curve was performed to predict accuracy of the model, meanwhile, a validation cohort from Fudan University Shanghai Cancer Center (FUSCC) was obtained to verify the signature. Then we estimated association between TMB and immune infiltrates by CIBERSORT algorithm and figured out prognostic immune cells of UCEC in TIMER database. Total 575 samples including 25 normal tissues and 552 tumor samples were enrolled from TCGA database. PTEN mutations accounted for the most and single nucleotide polymorphism and C>T transitions were most frequent forms of somatic mutations in UCEC. The low-TMB group possessed worse survival than the high-TMB group (P = 0.004). DEGs in 2 TMB groups were mostly enriched in adaptive immune response and immunoglobulin/immune receptor component. A TMB-related signature consisting of GFAP, EDN3, CXCR3, PLXNA4, SST presented good predictability with area under the curve (AUC) = 0.686. In FUSCC validation cohort, the high-risk group possessed worse survival outcome than the low-risk group (P = 0.015). Immune infiltrates was correlated to survival in UCEC and low TMB were associated with less immune infiltrates, which suggested poor immune response. TMB was not only related to overall survival but also immune infiltrates in UCEC. The TMB-related signature (GFAP, EDN3, CXCR3, PLXNA4, SST) had good predictability for overall survival in endometrial cancer. Our study might have some merits in elucidating potential mechanism of TMB and immune infiltrates in UCEC and providing guidance of immunotherapy for endometrial cancer.
探讨肿瘤突变负担（TMB）在子宫内膜癌中的预后价值及其与免疫浸润的相关性。从 TCGA 数据库下载了子宫内膜癌（UCEC）的转录组和体细胞突变谱。通过“maftools”分析体细胞突变，并以瀑布图可视化。我们计算了每位患者的 TMB，并通过中位数阈值将所有患者分为高 TMB 组和低 TMB 组。使用生存分析和 Wilcoxon 检验来研究 TMB 的预后价值及其与临床变量的关系。在 2 个 TMN 组中鉴定出差异表达基因（DEGs），并进行功能分析以找到显著的生物学途径。通过多元分析构建 TMB 相关特征，通过接收者操作特征（ROC）曲线预测模型的准确性，同时从复旦大学上海癌症中心（FUSCC）获得验证队列来验证特征。然后我们通过 CIBERSORT 算法估计 TMB 与免疫浸润之间的关联，并通过 TIMER 数据库确定 UCEC 的预后免疫细胞。从 TCGA 数据库共纳入 575 例样本，包括 25 例正常组织和 552 例肿瘤样本。PTEN 突变在 UCEC 中占比最多，体细胞突变最常见的形式是单核苷酸多态性和 C>T 转换。低 TMB 组的生存状况比高 TMB 组差（P=0.004）。2 个 TMB 组中的 DEGs 主要富集在适应性免疫反应和免疫球蛋白/免疫受体成分中。由 GFAP、EDN3、CXCR3、PLXNA4、SST 组成的 TMB 相关特征具有良好的预测能力，曲线下面积（AUC）为 0.686。在 FUSCC 验证队列中，高危组的生存结果比低危组差（P=0.015）。免疫浸润与 UCEC 的生存相关，低 TMB 与较少的免疫浸润相关，提示免疫反应较差。TMB 不仅与总生存率相关，而且与 UCEC 中的免疫浸润相关。TMB 相关特征（GFAP、EDN3、CXCR3、PLXNA4、SST）对子宫内膜癌的总生存率具有良好的预测能力。我们的研究可能在阐明 UCEC 中 TMB 和免疫浸润的潜在机制以及为子宫内膜癌的免疫治疗提供指导方面具有一定的价值。
Zotero 插件