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

Yun Rose Li, Kyle D. Halliwill, Cassandra J. Adams, Vivek Iyer, Laura Riva, Rashid Mamunur, Kuang-Yu Jen, Reyno Rosario, Erik Fredlund, Gillian Hirst, Ludmil B. Alexandrov, David Adams () and Allan Balmain ()
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Yun Rose Li: University of California San Francisco
Kyle D. Halliwill: University of California San Francisco
Cassandra J. Adams: University of California San Francisco
Vivek Iyer: Wellcome Trust Sanger Institute, Hinxton
Laura Riva: Wellcome Trust Sanger Institute, Hinxton
Rashid Mamunur: Wellcome Trust Sanger Institute, Hinxton
Kuang-Yu Jen: University of California San Francisco
Reyno Rosario: University of California San Francisco
Erik Fredlund: University of California San Francisco
Gillian Hirst: University of California San Francisco
Ludmil B. Alexandrov: University of California, San Diego
David Adams: Wellcome Trust Sanger Institute, Hinxton
Allan Balmain: University of California San Francisco

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14261-4

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