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Mutational signatures of ionizing radiation in second malignancies

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Publication Date: 2016-09-12

Journal Title: Nature Communications

Publisher: Nature Publishing Group

Volume: 7

Number: 12605

Language: English

Type: Article

This Version: VoR

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Citation: Behjati, S., Gundem, G., Wedge, D., Roberts, N., Tarpey, P., Cooke, S., Van Loo, P., et al. (2016). Mutational signatures of ionizing radiation in second malignancies. Nature Communications, 7 (12605)

Abstract: Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.

Sponsorship: This work was supported by funding from the Wellcome Trust (grant reference 077012/Z/05/Z), Skeletal Cancer Action Trust, Rosetrees Trust UK, Bone Cancer Research Trust, the RNOH NHS Trust, the National Institute for Health Research Health Protection Research Unit in Chemical and Radiation Hazards and Threats at Newcastle University in partnership with Public Health England. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. Tissue was obtained from the RNOH Musculoskeletal Research Programme and Biobank, co-ordinated by Mrs Deidre Brooking and Mrs Ru Grinnell, Biobank staff, RNOH. Support was provided to AMF by the National Institute for Health Research, UCLH Biomedical Research Centre, and the CRUK UCL Experimental Cancer Centre. S.N.Z. and S.B. are personally funded through Wellcome Trust Intermediate Clinical Research Fellowships, P.J.C. through a Wellcome Trust Senior Clinical Research Fellowship.


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Rights: Attribution 4.0 International

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Author: Behjati, SamGundem, GWedge, DCRoberts, NDTarpey, PSCooke, SLVan Loo, PAlexandrov, LBRamakrishna, MDavies, HNik-Zainal, SHardy, CLa



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