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

Abstract

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.

Profiling of urine bacterial DNA to identify an “oncobiome” in a mouse model of bladder cancer

“…Although the incidence of cancer is not 100%, this can be seen as an advantage given that an array of pathologies are obtained. Work by our group and others has shown that BBN-induced bladder cancers in mice closely resemble human cancers, both histologically [24], and by gene expression analysis, with a particular resemblance to muscle-invasive disease noted by several groups [25][26][27].…”

Antibody Targeting of B7-H4 Enhances the Immune Response in Urothelial Carcinoma

“…Until To identify potential immune regulatory mechanisms involved in the immune-editing of bladder cancer, we profiled the immune landscape of the mouse BBN bladder cancer model from 2 to 20 weeks. Our group has previously validated the genomic alterations that develop in this model (37). To our knowledge, we are the first to describe the immune activation that is bi-modal after BBN treatment.…”

“…To investigate the interaction between bladder cancer initiation and progression we used the syngeneic, carcinogen-induced mouse model of bladder cancer derived from timed exposure to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Our laboratory has previously validated the genomic credibility of this model that develops muscle-invasive bladder cancer (MIBC) between three and five months after initial exposure (37). Evaluation of the mutation signature most closely aligns with those caused by smoking, justifying the clinical relevance of BBN to bladder cancer, in which over 60% of cancers are attributed to smoking carcinogens (38).…”

MutSignatures: An R Package for Extraction and Analysis of Cancer Mutational Signatures

“…VCF files, which are typically used to record DNA variants, can be imported individually or in batch. Our framework allows import and analysis of mutation data aligned to human as well as non-human genomes, including the mouse mm10 assembly (21). By default, mutations types are formatted according to the style used by COSMIC and the Sanger Institute (for example, A| C>T|A).…”

“…This framework includes an R-ported version of the software developed by Alexandrov et al (12), accompanied by a wide set of functions for data import, preparation, analysis, and visualization. Notably, our software is compatible with nonhuman genomes, and was successfully employed to extract for the first time two mutational signatures from a carcinogen-induced mouse model of bladder cancer (21). Moreover, mutSignatures provides users with optional tools for inspecting non-standard mutation types, applying sample-wise mutation count normalization, and using a multiplicative update NMF algorithm (22) alternative to the standard Brunet's algorithm (13).…”