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Nat Commun. 2016 Sep 12;7:12605. doi: 10.1038/ncomms12605.

Mutational signatures of ionizing radiation in second malignancies.

Author information

1
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
2
Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.
3
Oxford Big Data Institute and Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
4
The Francis Crick Institute, London WC2A 3LY, UK.
5
Department of Human Genetics, University of Leuven, Leuven B-3000, Belgium.
6
University College London Cancer Institute, Huntley Street, London WC1E 6BT, UK.
7
Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
8
Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
9
Department of Genomic Medicine, MD Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA.
10
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Centre for Radiation Chemical and Environmental Hazards, Public Health England, Chilton, Didcot OX11 0RQ, UK.
11
Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere FI-33520, Finland.
12
Dana-Farber Cancer Institute, Boston, Massachusetts 02215-5450, USA.
13
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 USA.
14
Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK.

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.

PMID:
27615322
PMCID:
PMC5027243
DOI:
10.1038/ncomms12605
[Indexed for MEDLINE]
Free PMC Article

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