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Nat Commun. 2020 Jan 20;11(1):394. doi: 10.1038/s41467-019-14261-4.

Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice.

Author information

1
UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94158, USA.
2
Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.
3
Abbvie, Redwood City, CA, 94063, USA.
4
Nuffield Department of Medicine, University of Oxford, Oxford OX7DQ, UK.
5
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK.
6
Department of Pathology, University of California Davis Medical Center, Sacramento, CA, USA.
7
Doublestrand Bioinformatics, 11331, Stockholm, Sweden.
8
Department of Cellular and Molecular Medicine and Department of Bioengineering, Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
9
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK. da1@sanger.ac.uk.
10
UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94158, USA. allan.balmain@ucsf.edu.
11
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, 94158, USA. allan.balmain@ucsf.edu.

Abstract

Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (56Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.

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