Mutational signatures of ionizing radiation in second malignancies.
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.
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.|Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.
Sam
S
Behjati
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Gunes
G
Gundem
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.|Oxford Big Data Institute and Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
David C
DC
Wedge
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Nicola D
ND
Roberts
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Patrick S
PS
Tarpey
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Susanna L
SL
Cooke
The Francis Crick Institute, London WC2A 3LY, UK.|Department of Human Genetics, University of Leuven, Leuven B-3000, Belgium.
Peter
0000-0003-0292-1949
P
Van Loo
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Ludmil B
LB
Alexandrov
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Manasa
M
Ramakrishna
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Helen
H
Davies
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Serena
S
Nik-Zainal
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Claire
C
Hardy
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Calli
C
Latimer
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Keiran M
0000-0002-5634-1539
KM
Raine
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Lucy
L
Stebbings
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Andy
A
Menzies
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
David
D
Jones
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Rebecca
R
Shepherd
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Adam P
AP
Butler
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Jon W
JW
Teague
University College London Cancer Institute, Huntley Street, London WC1E 6BT, UK.
Mette
M
Jorgensen
Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
Bhavisha
B
Khatri
University College London Cancer Institute, Huntley Street, London WC1E 6BT, UK.|Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
Nischalan
N
Pillay
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.|Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
Adam
A
Shlien
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.|Department of Genomic Medicine, MD Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA.
P Andrew
PA
Futreal
Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Centre for Radiation Chemical and Environmental Hazards, Public Health England, Chilton, Didcot OX11 0RQ, UK.
Christophe
C
Badie
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Ultan
0000-0001-9032-4700
U
McDermott
Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere FI-33520, Finland.
G Steven
GS
Bova
Dana-Farber Cancer Institute, Boston, Massachusetts 02215-5450, USA.|Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 USA.
Andrea L
AL
Richardson
University College London Cancer Institute, Huntley Street, London WC1E 6BT, UK.|Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
Adrienne M
AM
Flanagan
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.
Michael R
MR
Stratton
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA UK.|Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK.
Peter J
PJ
Campbell
D001943:Breast Neoplasms; D004249:DNA Damage; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009154:Mutation; D016609:Neoplasms, Second Primary; D012516:Osteosarcoma; D011471:Prostatic Neoplasms; D011839:Radiation, Ionizing