Song Xiaodong, Xin Sheng, Zhang Yucong, Mao Jiaquan, Duan Chen, Cui Kai, Chen Liang, Li Fan, Liu Zheng, Wang Tao, Liu Jihong, Liu Xiaming, Song Wen
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Geriatric, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Cell Dev Biol. 2022 Feb 21;10:810272. doi: 10.3389/fcell.2022.810272. eCollection 2022.
The morbidity of bladder cancer (BLCA) is high and has gradually elevated in recent years. BLCA is also characterized by high recurrence and high invasiveness. Due to the drug resistance and lack of effective prognostic indicators, the prognosis of patients with BLCA is greatly affected. Iron metabolism is considered to be a pivot of tumor occurrence, progression, and tumor microenvironment (TME) in tumors, but there is little research in BLCA. Herein, we used univariate COX regression analysis to screen 95 prognosis-related iron metabolism-related genes (IMRGs) according to transcription RNA sequencing and prognosis information of the Cancer Genome Atlas (TCGA) database. TCGA-BLCA cohort was clustered into four distinct iron metabolism patterns (C1, C2, C3, and C4) by the non-negative matrix factorization (NMF) algorithm. Survival analysis showed that C1 and C3 patterns had a better prognosis. Gene set variant analysis (GSVA) revealed that C2 and C4 patterns were mostly enriched in carcinogenic and immune activation pathways. ESTIMATE and single sample gene set enrichment analysis (ssGSEA) also confirmed the level of immune cell infiltration in C2 and C4 patterns was significantly elevated. Moreover, the immune checkpoint genes in C2 and C4 patterns were observably overexpressed. Studies on somatic mutations showed that the tumor mutation burden (TMB) of C1 and C4 patterns was the lowest. Chemotherapy response assessment revealed that C2 pattern was the most sensitive to chemotherapy, while C3 pattern was the most insensitive. Then we established the IMRG prognosis signature (IMRGscore) by the least absolute shrinkage and selection operator (LASSO), including 13 IMRGs (TCIRG1, CTSE, ATP6V0A1, CYP2C8, RNF19A, CYP4Z1, YPEL5, PLOD1, BMP6, CAST, SCD, IFNG, and ASIC3). We confirmed IMRGscore could be utilized as an independent prognostic indicator. Therefore, validation and quantification of iron metabolism landscapes will help us comprehend the formation of the BLCA immunosuppressive microenvironment, guide the selection of chemotherapeutic drugs and immunotherapy, and predict the prognosis of patients.
膀胱癌（BLCA）的发病率较高，且近年来呈逐渐上升趋势。BLCA还具有高复发率和高侵袭性的特点。由于耐药性以及缺乏有效的预后指标，BLCA患者的预后受到极大影响。铁代谢被认为是肿瘤发生、发展及肿瘤微环境（TME）的关键因素，但在BLCA方面的研究较少。在此，我们根据癌症基因组图谱（TCGA）数据库的转录RNA测序和预后信息，采用单变量COX回归分析筛选出95个与预后相关的铁代谢相关基因（IMRGs）。通过非负矩阵分解（NMF）算法将TCGA - BLCA队列聚类为四种不同的铁代谢模式（C1、C2、C3和C4）。生存分析表明，C1和C3模式具有较好的预后。基因集变异分析（GSVA）显示，C2和C4模式大多富集于致癌和免疫激活途径。ESTIMATE和单样本基因集富集分析（ssGSEA）也证实，C2和C4模式中免疫细胞浸润水平显著升高。此外，C2和C4模式中的免疫检查点基因明显过表达。体细胞突变研究表明，C1和C4模式的肿瘤突变负担（TMB）最低。化疗反应评估显示，C2模式对化疗最敏感，而C3模式最不敏感。然后我们通过最小绝对收缩和选择算子（LASSO）建立了IMRG预后特征（IMRGscore），包括13个IMRGs（TCIRG1、CTSE、ATP6V0A1、CYP2C8、RNF19A、CYP4Z1、YPEL5、PLOD1、BMP6、CAST、SCD、IFNG和ASIC3）。我们证实IMRGscore可作为独立的预后指标。因此，铁代谢格局的验证和量化将有助于我们理解BLCA免疫抑制微环境的形成，指导化疗药物和免疫治疗的选择，并预测患者的预后。
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