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; Colin S. Cooper; Rosalind A. Eeles; Douglas Easton; Christopher Foster; David E. Neal; Daniel S. Brewer; Freddie Hamdy; Yong-Jie Lu; Andrew G. Lynch; Charlie E. Massi; Anthony Ng; Hayley C. Whitaker; Yongwei Yu; Hongwei Zhang; Elizabeth Bancroft; Dan Berney; Niedzica Camacho; Cathy Corbishley; Tokhir Dadaev; Nening Dennis; Tim Dudderidge; Sandra Edwards; Cyril Fisher; Jilur Ghori; Vincent J. Gnanapragasam; Christopher Greenman; Steve Hawkins; Steven Hazell; Will Howat; Katalin Karaszi; Jonathan Kay; Zsofia Kote-Jarai; Barbara Kremeyer; Pardeep Kumar; Adam Lambert; Daniel Leongamornlert; Naomi Livni; Hayley Luxton; Lucy Matthews; Erik Mayer; Susan Merson; David Nicol; Christopher Ogden; Sarah O'Meara; Gill Pelvender; Nimish C. Shah; Simon Tavare; Sarah Thomas; Alan Thompson; Claire Verrill; Anne Warren; Jorge Zamora; Ultan McDermott; G. Steven Bova; Andrea L. Richardson; Adrienne M. Flanagan; Michael R. Stratton; Peter J. Campbell

doi:10.1038/ncomms12605

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. TeagueMette Jorgensen, Bhavisha Khatri, Nischalan Pillay, Adam Shlien, P. Andrew Futreal, Christophe Badie, Colin S. Cooper, Rosalind A. Eeles, Douglas Easton, Christopher Foster, David E. Neal, Daniel S. Brewer, Freddie Hamdy, Yong-Jie Lu, Andrew G. Lynch, Charlie E. Massi, Anthony Ng, Hayley C. Whitaker, Yongwei Yu, Hongwei Zhang, Elizabeth Bancroft, Dan Berney, Niedzica Camacho, Cathy Corbishley, Tokhir Dadaev, Nening Dennis, Tim Dudderidge, Sandra Edwards, Cyril Fisher, Jilur Ghori, Vincent J. Gnanapragasam, Christopher Greenman, Steve Hawkins, Steven Hazell, Will Howat, Katalin Karaszi, Jonathan Kay, Zsofia Kote-Jarai, Barbara Kremeyer, Pardeep Kumar, Adam Lambert, Daniel Leongamornlert, Naomi Livni, Hayley Luxton, Lucy Matthews, Erik Mayer, Susan Merson, David Nicol, Christopher Ogden, Sarah O'Meara, Gill Pelvender, Nimish C. Shah, Simon Tavare, Sarah Thomas, Alan Thompson, Claire Verrill, Anne Warren, Jorge Zamora, Ultan McDermott, G. Steven Bova, Andrea L. Richardson, Adrienne M. Flanagan, Michael R. Stratton, Peter J. Campbell

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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.

Original language	English
Article number	12605
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12605
Publication status	Published - 12 Sep 2016

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Daniel Brewer
- D.Breweruea.acuk
- Norwich Medical School - Professor in Medical Bioinformatics and Genomics
- Metabolic Health - Member
- Cancer Studies - Member
Person: Research Group Member, Research Centre Member, Academic, Teaching & Research
Colin Cooper
- Colin.Cooperuea.acuk
- Norwich Medical School - Professor of Cancer Genetics
- Cancer Studies - Member
Person: Research Group Member, Academic, Teaching & Research
Christopher Greenman
- C.Greenmanuea.acuk
- School of Computing Sciences - Lecturer
- Centre for Photonics and Quantum Science - Member
- Computational Biology - Member
Person: Research Group Member, Academic, Teaching & Research

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Behjati, S., Gundem, G., Wedge, D. C., Roberts, N. D., Tarpey, P. S., Cooke, S. L., Van Loo, P., Alexandrov, L. B., Ramakrishna, M., Davies, H., Nik-Zainal, S., Hardy, C., Latimer, C., Raine, K. M., Stebbings, L., Menzies, A., Jones, D., Shepherd, R., Butler, A. P., ... Campbell, P. J. (2016). Mutational signatures of ionizing radiation in second malignancies. Nature Communications, 7, [12605]. https://doi.org/10.1038/ncomms12605

Behjati, Sam ; Gundem, Gunes ; Wedge, David C. ; Roberts, Nicola D. ; Tarpey, Patrick S. ; Cooke, Susanna L. ; Van Loo, Peter ; Alexandrov, Ludmil B. ; Ramakrishna, Manasa ; Davies, Helen ; Nik-Zainal, Serena ; Hardy, Claire ; Latimer, Calli ; Raine, Keiran M. ; Stebbings, Lucy ; Menzies, Andy ; Jones, David ; Shepherd, Rebecca ; Butler, Adam P. ; Teague, Jon W. ; Jorgensen, Mette ; Khatri, Bhavisha ; Pillay, Nischalan ; Shlien, Adam ; Futreal, P. Andrew ; Badie, Christophe ; Cooper, Colin S. ; Eeles, Rosalind A. ; Easton, Douglas ; Foster, Christopher ; Neal, David E. ; Brewer, Daniel S. ; Hamdy, Freddie ; Lu, Yong-Jie ; Lynch, Andrew G. ; Massi, Charlie E. ; Ng, Anthony ; Whitaker, Hayley C. ; Yu, Yongwei ; Zhang, Hongwei ; Bancroft, Elizabeth ; Berney, Dan ; Camacho, Niedzica ; Corbishley, Cathy ; Dadaev, Tokhir ; Dennis, Nening ; Dudderidge, Tim ; Edwards, Sandra ; Fisher, Cyril ; Ghori, Jilur ; Gnanapragasam, Vincent J. ; Greenman, Christopher ; Hawkins, Steve ; Hazell, Steven ; Howat, Will ; Karaszi, Katalin ; Kay, Jonathan ; Kote-Jarai, Zsofia ; Kremeyer, Barbara ; Kumar, Pardeep ; Lambert, Adam ; Leongamornlert, Daniel ; Livni, Naomi ; Luxton, Hayley ; Matthews, Lucy ; Mayer, Erik ; Merson, Susan ; Nicol, David ; Ogden, Christopher ; O'Meara, Sarah ; Pelvender, Gill ; Shah, Nimish C. ; Tavare, Simon ; Thomas, Sarah ; Thompson, Alan ; Verrill, Claire ; Warren, Anne ; Zamora, Jorge ; McDermott, Ultan ; Bova, G. Steven ; Richardson, Andrea L. ; Flanagan, Adrienne M. ; Stratton, Michael R. ; Campbell, Peter J. / Mutational signatures of ionizing radiation in second malignancies. In: Nature Communications. 2016 ; Vol. 7.

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title = "Mutational signatures of ionizing radiation in second malignancies",

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.",

author = "Sam Behjati and Gunes Gundem and Wedge, {David C.} and Roberts, {Nicola D.} and Tarpey, {Patrick S.} and Cooke, {Susanna L.} and {Van Loo}, Peter and Alexandrov, {Ludmil B.} and Manasa Ramakrishna and Helen Davies and Serena Nik-Zainal and Claire Hardy and Calli Latimer and Raine, {Keiran M.} and Lucy Stebbings and Andy Menzies and David Jones and Rebecca Shepherd and Butler, {Adam P.} and Teague, {Jon W.} and Mette Jorgensen and Bhavisha Khatri and Nischalan Pillay and Adam Shlien and Futreal, {P. Andrew} and Christophe Badie and Cooper, {Colin S.} and Eeles, {Rosalind A.} and Douglas Easton and Christopher Foster and Neal, {David E.} and Brewer, {Daniel S.} and Freddie Hamdy and Yong-Jie Lu and Lynch, {Andrew G.} and Massi, {Charlie E.} and Anthony Ng and Whitaker, {Hayley C.} and Yongwei Yu and Hongwei Zhang and Elizabeth Bancroft and Dan Berney and Niedzica Camacho and Cathy Corbishley and Tokhir Dadaev and Nening Dennis and Tim Dudderidge and Sandra Edwards and Cyril Fisher and Jilur Ghori and Gnanapragasam, {Vincent J.} and Christopher Greenman and Steve Hawkins and Steven Hazell and Will Howat and Katalin Karaszi and Jonathan Kay and Zsofia Kote-Jarai and Barbara Kremeyer and Pardeep Kumar and Adam Lambert and Daniel Leongamornlert and Naomi Livni and Hayley Luxton and Lucy Matthews and Erik Mayer and Susan Merson and David Nicol and Christopher Ogden and Sarah O'Meara and Gill Pelvender and Shah, {Nimish C.} and Simon Tavare and Sarah Thomas and Alan Thompson and Claire Verrill and Anne Warren and Jorge Zamora and Ultan McDermott and Bova, {G. Steven} and Richardson, {Andrea L.} and Flanagan, {Adrienne M.} and Stratton, {Michael R.} and Campbell, {Peter J.}",

note = "This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/",

year = "2016",

month = sep,

day = "12",

doi = "10.1038/ncomms12605",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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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, Cooper, CS, Eeles, RA, Easton, D, Foster, C, Neal, DE, Brewer, DS, Hamdy, F, Lu, Y-J, Lynch, AG, Massi, CE, Ng, A, Whitaker, HC, Yu, Y, Zhang, H, Bancroft, E, Berney, D, Camacho, N, Corbishley, C, Dadaev, T, Dennis, N, Dudderidge, T, Edwards, S, Fisher, C, Ghori, J, Gnanapragasam, VJ, Greenman, C, Hawkins, S, Hazell, S, Howat, W, Karaszi, K, Kay, J, Kote-Jarai, Z, Kremeyer, B, Kumar, P, Lambert, A, Leongamornlert, D, Livni, N, Luxton, H, Matthews, L, Mayer, E, Merson, S, Nicol, D, Ogden, C, O'Meara, S, Pelvender, G, Shah, NC, Tavare, S, Thomas, S, Thompson, A, Verrill, C, Warren, A, Zamora, J, McDermott, U, Bova, GS, Richardson, AL, Flanagan, AM, Stratton, MR & Campbell, PJ 2016, 'Mutational signatures of ionizing radiation in second malignancies', Nature Communications, vol. 7, 12605. https://doi.org/10.1038/ncomms12605

Mutational signatures of ionizing radiation in second malignancies. / Behjati, Sam; Gundem, Gunes; Wedge, David C.; Roberts, Nicola D.; Tarpey, Patrick S.; Cooke, Susanna L.; Van Loo, Peter; Alexandrov, Ludmil B.; Ramakrishna, Manasa; Davies, Helen; Nik-Zainal, Serena; Hardy, Claire; Latimer, Calli; Raine, Keiran M.; Stebbings, Lucy; Menzies, Andy; Jones, David; Shepherd, Rebecca; Butler, Adam P.; Teague, Jon W.; Jorgensen, Mette; Khatri, Bhavisha; Pillay, Nischalan; Shlien, Adam; Futreal, P. Andrew; Badie, Christophe; Cooper, Colin S.; Eeles, Rosalind A.; Easton, Douglas; Foster, Christopher; Neal, David E.; Brewer, Daniel S.; Hamdy, Freddie; Lu, Yong-Jie; Lynch, Andrew G.; Massi, Charlie E.; Ng, Anthony; Whitaker, Hayley C.; Yu, Yongwei; Zhang, Hongwei; Bancroft, Elizabeth; Berney, Dan; Camacho, Niedzica; Corbishley, Cathy; Dadaev, Tokhir; Dennis, Nening; Dudderidge, Tim; Edwards, Sandra; Fisher, Cyril; Ghori, Jilur; Gnanapragasam, Vincent J.; Greenman, Christopher; Hawkins, Steve; Hazell, Steven; Howat, Will; Karaszi, Katalin; Kay, Jonathan; Kote-Jarai, Zsofia; Kremeyer, Barbara; Kumar, Pardeep; Lambert, Adam; Leongamornlert, Daniel; Livni, Naomi; Luxton, Hayley; Matthews, Lucy; Mayer, Erik; Merson, Susan; Nicol, David; Ogden, Christopher; O'Meara, Sarah; Pelvender, Gill; Shah, Nimish C.; Tavare, Simon; Thomas, Sarah; Thompson, Alan; Verrill, Claire; Warren, Anne; Zamora, Jorge; McDermott, Ultan; Bova, G. Steven; Richardson, Andrea L.; Flanagan, Adrienne M.; Stratton, Michael R.; Campbell, Peter J.

In: Nature Communications, Vol. 7, 12605, 12.09.2016.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Mutational signatures of ionizing radiation in second malignancies

AU - Behjati, Sam

AU - Gundem, Gunes

AU - Wedge, David C.

AU - Roberts, Nicola D.

AU - Tarpey, Patrick S.

AU - Cooke, Susanna L.

AU - Van Loo, Peter

AU - Alexandrov, Ludmil B.

AU - Ramakrishna, Manasa

AU - Davies, Helen

AU - Nik-Zainal, Serena

AU - Hardy, Claire

AU - Latimer, Calli

AU - Raine, Keiran M.

AU - Stebbings, Lucy

AU - Menzies, Andy

AU - Jones, David

AU - Shepherd, Rebecca

AU - Butler, Adam P.

AU - Teague, Jon W.

AU - Jorgensen, Mette

AU - Khatri, Bhavisha

AU - Pillay, Nischalan

AU - Shlien, Adam

AU - Futreal, P. Andrew

AU - Badie, Christophe

AU - Cooper, Colin S.

AU - Eeles, Rosalind A.

AU - Easton, Douglas

AU - Foster, Christopher

AU - Neal, David E.

AU - Brewer, Daniel S.

AU - Hamdy, Freddie

AU - Lu, Yong-Jie

AU - Lynch, Andrew G.

AU - Massi, Charlie E.

AU - Ng, Anthony

AU - Whitaker, Hayley C.

AU - Yu, Yongwei

AU - Zhang, Hongwei

AU - Bancroft, Elizabeth

AU - Berney, Dan

AU - Camacho, Niedzica

AU - Corbishley, Cathy

AU - Dadaev, Tokhir

AU - Dennis, Nening

AU - Dudderidge, Tim

AU - Edwards, Sandra

AU - Fisher, Cyril

AU - Ghori, Jilur

AU - Gnanapragasam, Vincent J.

AU - Greenman, Christopher

AU - Hawkins, Steve

AU - Hazell, Steven

AU - Howat, Will

AU - Karaszi, Katalin

AU - Kay, Jonathan

AU - Kote-Jarai, Zsofia

AU - Kremeyer, Barbara

AU - Kumar, Pardeep

AU - Lambert, Adam

AU - Leongamornlert, Daniel

AU - Livni, Naomi

AU - Luxton, Hayley

AU - Matthews, Lucy

AU - Mayer, Erik

AU - Merson, Susan

AU - Nicol, David

AU - Ogden, Christopher

AU - O'Meara, Sarah

AU - Pelvender, Gill

AU - Shah, Nimish C.

AU - Tavare, Simon

AU - Thomas, Sarah

AU - Thompson, Alan

AU - Verrill, Claire

AU - Warren, Anne

AU - Zamora, Jorge

AU - McDermott, Ultan

AU - Bova, G. Steven

AU - Richardson, Andrea L.

AU - Flanagan, Adrienne M.

AU - Stratton, Michael R.

AU - Campbell, Peter J.

N1 - This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

PY - 2016/9/12

Y1 - 2016/9/12

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms12605

DO - 10.1038/ncomms12605

M3 - Article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 12605

ER -

Mutational signatures of ionizing radiation in second malignancies

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Daniel Brewer

Colin Cooper

Christopher Greenman

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