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Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma

Nature Medicine volume 21, pages 946–954 (2015)Cite this article

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Abstract

Mouse models of cancers are routinely used to study cancer biology. However, it remains unclear whether carcinogenesis in mice is driven by the same spectrum of genomic alterations found in humans. Here we conducted a comprehensive genomic analysis of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced skin cancer, the most commonly used skin cancer model, which appears as benign papillomas that progress into squamous cell carcinomas (SCCs). We also studied genetically induced SCCs that expressed G12D mutant Kras (Kras G12D) but were deficient for p53. Using whole-exome sequencing, we uncovered a characteristic mutational signature of DMBA-induced SCCs. We found that the vast majority of DMBA-induced SCCs presented recurrent mutations in Hras, Kras or Rras2 and mutations in several additional putative oncogenes and tumor-suppressor genes. Similar genes were recurrently mutated in mouse and human SCCs that were from different organs or had been exposed to different carcinogens. Invasive SCCs, but not papillomas, presented substantial chromosomal aberrations, especially in DMBA-induced and genetically induced Trp53-mutated SCCs. Metastasis occurred through sequential spreading, with relatively few additional genetic events. This study provides a framework for future functional cancer genomic studies in mice.

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Figure 1: Mutational signature of DMBA-TPA–induced msSCCs.
Figure 2: Recurrent somatic mutations in DMBA-induced msSCCs.
Figure 3: Recurrent CNAs in DMBA-induced and genetically induced msSCC.
Figure 4: Histological heterogeneity of DMBA-induced msSCCs.
Figure 5: Clonal evolution in primary and metastatic DMBA-induced msSCC.

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Acknowledgements

C.B. is an investigator at Walloon Excellence in Life Sciences and Biotechnology (WELBIO). D.N. and M.L. are supported by Télévie and an EMBO long-term fellowship, respectively. The computational resources and services used in this work were provided by the Flemish Supercomputer Center (VSC), funded by the Hercules Foundation and the Flemish Government, Department of Economy, Science and Innovation (EWI). This work was supported by Fonds de la Recherche Scientifique (FNRS), Télévie, the Interuniversity Attraction Program (PAI), a research grant and an infrastructure grant from Fondation Contre le Cancer/Stichting tegen Kanker, Fondation ULB, Fond Yvonne Boël, Fond Gaston Ithier, the the Baillet Latour Foundation and the European Research Council (ERC).

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Author notes

  1. Dany Nassar, Mathilde Latil and Bram Boeckx: These authors contributed equally to this work.

  2. Diether Lambrechts and Cédric Blanpain: These authors jointly directed this work.

Authors and Affiliations

  1. Institut de recherche interdisciplinaire en biologie humaine et moléculaire (IRIBHM), Université libre de Buxelles (ULB), Brussels, Belgium

    Dany Nassar, Mathilde Latil & Cédric Blanpain

  2. Vesalius Research Center, Vlaams Instituut voor Biotechnologie VIB, Leuven, Belgium

    Bram Boeckx & Diether Lambrechts

  3. Department of Oncology, Laboratory for Translational Genetics, Katholieke Universiteit Leuven (KUL), Leuven, Belgium

    Bram Boeckx & Diether Lambrechts

  4. WELBIO, Brussels, Belgium

    Cédric Blanpain

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  1. Dany Nassar
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Contributions

C.B., D.N. and D.L. designed the experiments. B.B. and D.L. performed bioinformatic analysis. D.N. and M.L. performed biological experiments. All authors performed data analysis. C.B., D.L. and D.N. wrote the manuscript.

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Correspondence to Diether Lambrechts or Cédric Blanpain.

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Nassar, D., Latil, M., Boeckx, B. et al. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat Med 21, 946–954 (2015). https://doi.org/10.1038/nm.3878

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