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 Shilatifard & 1 others Joshua J Meeks*

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Citations (Scopus)

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

Fingerprint

Molecular Models
Urinary Bladder Neoplasms
Carcinogens
Muscles
Neoplasms
Mutation
Butylhydroxybutylnitrosamine
Genome
Exome
Atlases
Mutation Rate
Drug Discovery
Computational Biology
Chromatin
Immune System
Histology
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Fantini, Damiano ; Glaser, Alexander P. ; Rimar, Kalen J. ; Wang, Yiduo ; Schipma, Matthew John ; Varghese, Nobish ; Rademaker, Alfred W ; Behdad, Amir ; Yellapa, Aparna ; Yu, Yanni ; Sze, Christie Ching Lin ; Wang, Lu ; Zhao, Zibo ; Crawford, Susan E. ; Hu, Deqing ; Licht, Jonathan D. ; Collings, Clayton K. ; Bartom, Elizabeth Thomas ; Theodorescu, Dan ; Shilatifard, Ali ; Meeks, Joshua J. / A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer. In: Oncogene. 2018 ; Vol. 37, No. 14. pp. 1911-1925.
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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.",
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Fantini, D, Glaser, AP, Rimar, KJ, Wang, Y, Schipma, MJ, Varghese, N, Rademaker, AW, Behdad, A, Yellapa, A, Yu, Y, Sze, CCL, Wang, L, Zhao, Z, Crawford, SE, Hu, D, Licht, JD, Collings, CK, Bartom, ET, Theodorescu, D, Shilatifard, A & Meeks, JJ 2018, 'A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer', Oncogene, vol. 37, no. 14, pp. 1911-1925. https://doi.org/10.1038/s41388-017-0099-6

A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer. / Fantini, Damiano; Glaser, Alexander P.; Rimar, Kalen J.; Wang, Yiduo; Schipma, Matthew John; Varghese, Nobish; Rademaker, Alfred W; Behdad, Amir; Yellapa, Aparna; Yu, Yanni; Sze, Christie Ching Lin; Wang, Lu; Zhao, Zibo; Crawford, Susan E.; Hu, Deqing; Licht, Jonathan D.; Collings, Clayton K.; Bartom, Elizabeth Thomas; Theodorescu, Dan; Shilatifard, Ali; Meeks, Joshua J.

In: Oncogene, Vol. 37, No. 14, 01.04.2018, p. 1911-1925.

Research output: Contribution to journalArticle

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T1 - A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer

AU - Fantini, Damiano

AU - Glaser, Alexander P.

AU - Rimar, Kalen J.

AU - Wang, Yiduo

AU - Schipma, Matthew John

AU - Varghese, Nobish

AU - Rademaker, Alfred W

AU - Behdad, Amir

AU - Yellapa, Aparna

AU - Yu, Yanni

AU - Sze, Christie Ching Lin

AU - Wang, Lu

AU - Zhao, Zibo

AU - Crawford, Susan E.

AU - Hu, Deqing

AU - Licht, Jonathan D.

AU - Collings, Clayton K.

AU - Bartom, Elizabeth Thomas

AU - Theodorescu, Dan

AU - Shilatifard, Ali

AU - Meeks, Joshua J

PY - 2018/4/1

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N2 - 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.

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