Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-14261-4
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Funding
- Cancer Research UK Grand Challenge Award [C98/A24032]
- US National Cancer Institute (NCI) [RO1CA184510, UO1CA176287, R35CA210018]
- Barbara Bass Bakar Professorship of Cancer Genetics
- NASA [NNXD 9AM52G]
- DOE [DE-SC0003679]
- CRUK Program Grant
- NCI [F32 CA 232635, U01 CA 84244, F31 CA 180715]
- NIH [T32 GM 7175-35]
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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 (Fe-56-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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