A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer.

Animals; Carcinogens; Carcinoma, Transitional Cell; Cell Transformation, Neoplastic; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred C57BL; Microarray Analysis; Muscle Neoplasms; Mutation; Neoplasm Invasiveness; Transcriptome; Urinary Bladder Neoplasms

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.