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Oncogene. 2018 Apr;37(14):1911-1925. doi: 10.1038/s41388-017-0099-6. Epub 2018 Jan 25.

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

Author information

1
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
2
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
3
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
4
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
5
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
6
Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO, USA.
7
Department of Medicine, Division of Hematology and Oncology, University of Florida, Gainesville, FL, USA.
8
Department of Surgery (Urology) and Pharmacology, Comprehensive Cancer Center, University of Colorado, Denver, CO, USA.
9
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. joshua.meeks@northwestern.edu.
10
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. joshua.meeks@northwestern.edu.

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.

PMID:
29367767
PMCID:
PMC5886988
DOI:
10.1038/s41388-017-0099-6
[Indexed for MEDLINE]
Free PMC Article

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