Mutational signatures of ionizing radiation in second malignancies.
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Date
2016-09-12Author
Behjati, S
Gundem, G
Wedge, DC
Roberts, ND
Tarpey, PS
Cooke, SL
Van Loo, P
Alexandrov, LB
Ramakrishna, M
Davies, H
Nik-Zainal, S
Hardy, C
Latimer, C
Raine, KM
Stebbings, L
Menzies, A
Jones, D
Shepherd, R
Butler, AP
Teague, JW
Jorgensen, M
Khatri, B
Pillay, N
Shlien, A
Futreal, PA
Badie, C
ICGC Prostate Group,
McDermott, U
Bova, GS
Richardson, AL
Flanagan, AM
Stratton, MR
Campbell, PJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
ICGC Prostate Group
Humans
Osteosarcoma
Breast Neoplasms
Prostatic Neoplasms
Neoplasms, Second Primary
DNA Damage
Gene Deletion
Mutation
Germ-Line Mutation
Radiation, Ionizing
Female
Male
Research team
Oncogenetics
Language
eng
Date accepted
2016-07-13
License start date
2016-09-12
Citation
Nature communications, 2016, 7 pp. 12605 - ?
Publisher
NATURE PUBLISHING GROUP