Background Muscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice. Methods This study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t-test and fold change methods were used to perform the differential expression analysis. The hypergeometric test was used to test the enrichment of the differentially expressed genes in GO terms or KEGG pathways. Results In the present study, we identified three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle-invasive bladder cancer (MIBC) risk prediction. The validation of this stratification method on two datasets demonstrated that the stratified patients exhibited significant difference in overall survival, and our stratification was superior to three other stratifications. Consistently, the high-risk group exhibited worse prognosis than low-risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high-risk MIBC were significantly enriched in several cancer-related pathways. Notably, PDGFRB, a receptor for platelet-derived growth factor of PI3K-Akt signaling pathway, and TUBA1A were identified as two targets of multiple drugs. In addition, the angiogenesis-related genes, as well as two marker genes of M2 macrophage, CD163 and MRC1, were highly upregulated in high-risk MIBC. Conclusions In summary, this study investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of progression of MIBC and provide new therapeutic strategies for the MIBC patients.

中文翻译：

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基因表达谱的系统分析揭示了肌肉浸润性膀胱癌的预后分层和潜在机制。

背景 肌层浸润性膀胱癌 (MIBC) 起源于膀胱的肌肉壁，是全球第九大最常见的恶性肿瘤。然而，目前还没有可靠、准确和稳健的基因特征用于 MIBC 预后预测，这对于协助肿瘤科医生在临床实践中进行更准确的评估具有重要意义。方法本研究分别使用单变量和多变量Cox回归模型选择基因特征并建立风险预测模型。t检验和倍数变化方法用于进行差异表达分析。超几何测试用于测试GO术语或KEGG途径中差异表达基因的富集。结果 在本研究中，我们确定了三个预后基因 KLK6、TNS1 和 TRIM56，作为肌肉浸润性膀胱癌（MIBC）风险预测的最佳基因子集。这种分层方法在两个数据集上的验证表明，分层患者的总体生存率存在显着差异，我们的分层优于其他三个分层。一致地，在有和没有淋巴结转移、远处转移和放射治疗的样本中，高风险组的预后比低风险组差。此外，高危 MIBC 中上调的基因在几种癌症相关途径中显着富集。值得注意的是，PI3K-Akt 信号通路的血小板衍生生长因子受体 PDGFRB 和 TUBA1A 被确定为多种药物的两个靶点。此外，血管生成相关基因，以及 M2 巨噬细胞的两个标记基因，CD163 和 MRC1 在高风险 MIBC 中高度上调。结论 综上所述，本研究探讨了与高危 MIBC 预后较差相关的潜在分子机制和潜在治疗靶点，有助于加深我们对 MIBC 进展的认识，为 MIBC 患者提供新的治疗策略。