Cigarette smoking causes multiple cancers by directly influencing mutation burden of driver mutations. However, the mechanism between somatic mutation caused by cigarette smoking and bladder tumorigenesis remains elusive. Smoking‐related mutation profile of bladder cancer was characterized by The Cancer Genome Atlas cohort. Integraticve OncoGenomics database was utilized to detect the smoking‐related driver genes, and its biological mechanism predictions were interpreted based on bulk transcriptome and single‐cell transcriptome, as well as cell experiments. Cigarette smoking was associated with an increased tumor mutational burden under 65 years old (p = 0.031), and generated specific mutational signatures in smokers. RB1 was identified as a differentially mutated driver gene between smokers and nonsmokers, and the mutation rate of RB1 increased twofold after smoking (p = 0.008). RB1 mutations and the 4‐aminobiphenyl interference could significantly decrease the RB1 expression level and thus promote the proliferation, invasion, and migration ability of bladder cancer cells. Enrichment analysis and real‐time quantitative PCR (RT‐qPCR) data showed that RB1 mutations inhibited cytochrome P450 pathway by reducing expression levels of UGT1A6 and AKR1C2. In addition, we also observed that the component of immunological cells was regulated by RB1 mutations through the stronger cell‐to‐cell interactions between epithelial scissor+ cells and immune cells in smokers. This study highlighted that RB1 mutations could drive smoking‐related bladder tumorigenesis through inhibiting cytochrome P450 pathway and regulating tumor immune microenvironment.

中文翻译：

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RB1 突变通过调节细胞色素 P450 通路诱导吸烟相关膀胱癌


吸烟通过直接影响驱动突变的突变负荷导致多种癌症。然而，吸烟引起的体细胞突变与膀胱肿瘤发生之间的机制仍然难以捉摸。膀胱癌的吸烟相关突变谱由癌症基因组图谱队列表征。利用 Integraticve OncoGenomics 数据库检测吸烟相关驱动基因，并根据大量转录组和单细胞转录组以及细胞实验解释其生物学机制预测。吸烟与 65 岁以下肿瘤突变负荷增加相关 （p = 0.031），并在吸烟者中产生特异性突变特征。RB1 被鉴定为吸烟者和非吸烟者之间的差异突变驱动基因，吸烟后 RB1 的突变率增加了两倍 （p = 0.008）。RB1 突变和 4-氨基联苯干扰可显著降低 RB1 表达水平，从而促进膀胱癌细胞的增殖、侵袭和迁移能力。富集分析和实时定量 PCR （RT-qPCR） 数据显示，RB1 突变通过降低 UGT1A6 和 AKR1C2 的表达水平来抑制细胞色素 P450 通路。此外，我们还观察到免疫细胞的成分通过吸烟者上皮剪刀 + 细胞和免疫细胞之间更强的细胞间相互作用受 RB1 突变的调节。本研究强调 RB1 突变可通过抑制细胞色素 P450 通路和调节肿瘤免疫微环境来驱动吸烟相关的膀胱肿瘤发生。