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 del Rosario, Erik Fredlund, Gillian Hirst, Ludmil B. Alexandrov, David Adams, Allan Balmain

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1 Scopus citations

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.

Original languageEnglish (US)
Article number394
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Rose Li, Y., Halliwill, K. D., Adams, C. J., Iyer, V., Riva, L., Mamunur, R., Jen, K. Y., del Rosario, R., Fredlund, E., Hirst, G., Alexandrov, L. B., Adams, D., & Balmain, A. (2020). Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice. Nature communications, 11(1), [394]. https://doi.org/10.1038/s41467-019-14261-4