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

被引：49

作者：

Li, Yun Rose ^{[1
,2
]}

Halliwill, Kyle D. ^{[1
,3
]}

Adams, Cassandra J. ^{[1
,4
]}

Iyer, Vivek ^{[5
]}

Riva, Laura ^{[5
]}

Mamunur, Rashid ^{[5
]}

Jen, Kuang-Yu ^{[1
,6
]}

del Rosario, Reyno ^{[1
]}

Fredlund, Erik ^{[1
,7
]}

Hirst, Gillian ^{[1
]}

Alexandrov, Ludmil B. ^{[8
,9
]}

Adams, David ^{[5
]}

Balmain, Allan ^{[1
,10
]}

机构：

[1] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA

[3] AbbVie, Redwood City, CA 94063 USA

[4] Univ Oxford, Nuffield Dept Med, Oxford OX7 DQ, England

[5] Wellcome Trust Sanger Inst, Expt Canc Genet, Cambridge CB10 1HH, England

[6] Univ Calif Davis, Davis Med Ctr, Dept Pathol, Sacramento, CA 95817 USA

[7] Doublestrand Bioinformat, S-11331 Stockholm, Sweden

[8] Univ Calif San Diego, Moores Canc Ctr, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[9] Univ Calif San Diego, Moores Canc Ctr, Dept Bioengn, La Jolla, CA 92093 USA

[10] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

PROLINE-RICH DOMAIN; CANCER-RISK; DNA-DAMAGE; P53; REARRANGEMENTS; INSTABILITY; CARCINOGENESIS; SUSCEPTIBILITY; CHROMOTHRIPSIS; PREDICTION;

D O I：

10.1038/s41467-019-14261-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

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