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

Damiano Fantini, Alexander P. Glaser, Kalen J. Rimar, Yiduo Wang, Matthew John Schipma, Nobish Varghese, Alfred W Rademaker, Amir Behdad, Aparna Yellapa, Yanni Yu, Christie Ching Lin Sze, Lu Wang, Zibo Zhao, Susan E. Crawford, Deqing Hu, Jonathan D. Licht, Clayton K. Collings, Elizabeth Thomas Bartom, Dan Theodorescu, Ali ShilatifardJoshua J Meeks*

*Corresponding author for this work

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1911-1925
Number of pages15
JournalOncogene
Volume37
Issue number14
DOIs
StatePublished - Apr 1 2018

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Fantini, D., Glaser, A. P., Rimar, K. J., Wang, Y., Schipma, M. J., Varghese, N., Rademaker, A. W., Behdad, A., Yellapa, A., Yu, Y., Sze, C. C. L., Wang, L., Zhao, Z., Crawford, S. E., Hu, D., Licht, J. D., Collings, C. K., Bartom, E. T., Theodorescu, D., ... Meeks, J. J. (2018). A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer. Oncogene, 37(14), 1911-1925. https://doi.org/10.1038/s41388-017-0099-6