Mutational landscape of a chemically-induced mouse model of liver cancer.
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Authors
Rayner, Tim F
Aitken, Sarah J
Lukk, Margus
Santoyo-Lopez, Javier
Odom, Duncan T
Publication Date
2018-10Journal Title
J Hepatol
ISSN
0168-8278
Publisher
Elsevier BV
Volume
69
Issue
4
Pages
840-850
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Connor, F., Rayner, T. F., Aitken, S. J., Feig, C., Lukk, M., Santoyo-Lopez, J., & Odom, D. T. (2018). Mutational landscape of a chemically-induced mouse model of liver cancer.. J Hepatol, 69 (4), 840-850. https://doi.org/10.1016/j.jhep.2018.06.009
Abstract
BACKGROUND & AIMS: Carcinogen-induced mouse models of liver cancer are used extensively to study the pathogenesis of the disease and are critical for validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the genomic alterations driving these mouse tumour genomes are comparable to those found in human tumours. Herein, we provide a detailed genomic characterisation of tumours from a commonly used mouse model of hepatocellular carcinoma (HCC). METHODS: We analysed whole exome sequences of liver tumours arising in mice exposed to diethylnitrosamine (DEN). Mutational signatures were compared between liver tumours from DEN-treated and untreated mice, and human HCCs. RESULTS: DEN-initiated tumours had a high, uniform number of somatic single nucleotide variants (SNVs), with few insertions, deletions or copy number alterations, consistent with the known genotoxic action of DEN. Exposure of hepatocytes to DEN left a reproducible mutational imprint in resulting tumour exomes which we could computationally reconstruct using six known COSMIC mutational signatures. The tumours carried a high diversity of low-incidence, non-synonymous point mutations in many oncogenes and tumour suppressors, reflecting the stochastic introduction of SNVs into the hepatocyte genome by the carcinogen. We identified four recurrently mutated genes that were putative oncogenic drivers of HCC in this model. Every neoplasm carried activating hotspot mutations either in codon 61 of Hras, in codon 584 of Braf or in codon 254 of Egfr. Truncating mutations of Apc occurred in 21% of neoplasms, which were exclusively carcinomas supporting a role for deregulation of Wnt/β-catenin signalling in cancer progression. CONCLUSIONS: Our study provides detailed insight into the mutational landscape of tumours arising in a commonly used carcinogen model of HCC, facilitating the future use of this model to better understand the human disease. LAY SUMMARY: Mouse models are widely used to study the biology of cancer and to test potential therapies. Herein, we have described the mutational landscape of tumours arising in a carcinogen-induced mouse model of liver cancer. Since cancer is a disease caused by genomic alterations, information about the patterns and types of mutations in the tumours in this mouse model should facilitate its use to study human liver cancer.
Keywords
Cancer genomics, Carcinogen mouse model, Hepatocellular carcinoma, Hras, Mutational signatures, Animals, DNA Copy Number Variations, Diethylnitrosamine, Disease Models, Animal, Exome, Genes, ras, Liver Neoplasms, Experimental, Male, Mice, Mice, Inbred C3H, Mutation
Sponsorship
Cancer Research UK (core award 20412 and strategic award 22398)
The Wellcome Trust (106563/Z/14/A)
European Research Council (615584)
Funder references
European Research Council (615584)
Cancer Research UK (22398)
Cancer Research UK (C14303/A17197)
Cancer Research UK (unknown)
Cancer Research UK (20412)
Identifiers
External DOI: https://doi.org/10.1016/j.jhep.2018.06.009
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283461
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