Mutational signatures of ionizing radiation in second malignancies

Sam Behjati, Gunes Gundem, David C. Wedge, Nicola D. Roberts, Patrick S. Tarpey, Susanna L. Cooke, Peter Van Loo, Ludmil B. Alexandrov, Manasa Ramakrishna, Helen Davies, Serena Nik-Zainal, Claire Hardy, Calli Latimer, Keiran M. Raine, Lucy Stebbings, Andy Menzies, David Jones, Rebecca Shepherd, Adam P. Butler, Jon W. Teague, Mette Jorgensen, Bhavisha Khatri, Nischalan Pillay, Adam Shlien, P. Andrew Futreal, Christophe Badie, Ultan McDermott, G. Steven Bova, Andrea L. Richardson, Adrienne M. Flanagan, Michael R. Stratton and Peter J. Campbell ()
Additional contact information
Sam Behjati: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Gunes Gundem: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
David C. Wedge: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Nicola D. Roberts: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Patrick S. Tarpey: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Susanna L. Cooke: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Peter Van Loo: The Francis Crick Institute
Ludmil B. Alexandrov: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Manasa Ramakrishna: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Helen Davies: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Serena Nik-Zainal: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Claire Hardy: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Calli Latimer: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Keiran M. Raine: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Lucy Stebbings: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Andy Menzies: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
David Jones: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Rebecca Shepherd: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Adam P. Butler: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Jon W. Teague: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Mette Jorgensen: University College London Cancer Institute
Bhavisha Khatri: Histopathology, Royal National Orthopaedic Hospital NHS Trust
Nischalan Pillay: University College London Cancer Institute
Adam Shlien: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
P. Andrew Futreal: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Christophe Badie: Cancer Mechanisms and Biomarkers Group, Centre for Radiation Chemical and Environmental Hazards, Public Health England
Ultan McDermott: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
G. Steven Bova: Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital
Andrea L. Richardson: Dana-Farber Cancer Institute
Adrienne M. Flanagan: University College London Cancer Institute
Michael R. Stratton: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Peter J. Campbell: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12605

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