The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.

中文翻译：

---

致癌物诱发的小鼠模型概括了人类肌肉浸润性膀胱癌的分子变化。

N-丁基-N-（4-羟丁基）-亚硝胺（BBN）小鼠模型是一种肌肉侵袭性膀胱癌（MIBC）的有吸引力的模型系统，因为它在完整的免疫系统背景下概述了人类肿瘤的组织学。但是，尚不清楚这种致癌物诱导的模型是否还在分子和突变水平上模仿了人MIBC。在我们的研究中，我们使用癌症基因组图谱和其他存储库的数据，通过下一代测序，然后与人MIBC进行了生物信息学比较，分析了BBN模型的基因表达和突变情况。BBN肿瘤显示出基础癌亚型标志物的过表达，并且具有高突变负担，通过外显子组测序发现频繁的Trp53（80％），Kmt2d（70％）和Kmt2c（90％）突变，类似于人MIBC。许多变异对应人类癌症的热点突变，支持其作为驱动程序突变的角色。我们从BBN小鼠基因组中提取了两个新颖的突变特征。突变频率和特征的综合分析突出了畸变对BBN肿瘤中染色质调节剂和遗传不稳定性的贡献。总之，我们的研究揭示了人MIBC与BBN小鼠模型之间的一些相似之处，为在分子和药物发现研究中使用它提供了有力的依据。