Signatures of mutational processes in human cancer

Ludmil B. Alexandrov; Serena Nik-Zainal; David C. Wedge; Samuel A. J. R. Aparicio; Sam Behjati; Andrew V. Biankin; Graham R. Bignell; Niccolò Bolli; Ake Borg; Anne-Lise Børresen-Dale; Sandrine Boyault; Birgit Burkhardt; Adam P. Butler; Carlos Caldas; Helen R. Davies; Christine Desmedt; Roland Eils; Jórunn Erla Eyfjörd; John A. Foekens; Mel Greaves; Fumie Hosoda; Barbara Hutter; Tomislav Ilicic; Sandrine Imbeaud; Marcin Imielinski; Natalie Jäger; David T. W. Jones; David Jones; Stian Knappskog; Marcel Kool; Sunil R. Lakhani; Carlos López-Otín; Sancha Martin; Nikhil C Munshi; Hiromi Nakamura; Paul A. Northcott; Marina Pajic; Elli Papaemmanuil; Angelo Paradiso; John V. Pearson; Xose S. Puente; Keiran Raine; Manasa Ramakrishna; Andrea L. Richardson; Julia Richter; Philip Rosenstiel; Matthias Schlesner; Ton N. Schumacher; Paul N. Span; Jon W. Teague; Yasushi Totoki; Andrew N. J. Tutt; Rafael Valdés-Mas; Marit M. van Buuren; Laura van 't Veer; Anne Vincent-Salomon; Nicola Waddell; Lucy R. Yates; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain; Jessica Zucman-Rossi; P. Andrew Futreal; Ultan McDermott; Peter Lichter; Matthew Meyerson; Sean M. Grimmond; Reiner Siebert; Elías Campo; Tatsuhiro Shibata; Stefan M. Pfister; Peter J. Campbell; Michael R. Stratton

doi:10.1038/nature12477

Signatures of mutational processes in human cancer

Ludmil B. Alexandrov, Serena Nik-Zainal, David C. Wedge, Samuel A. J. R. Aparicio, Sam Behjati, Andrew V. Biankin, Graham R. Bignell, Niccolò Bolli, Ake Borg, Anne-Lise Børresen-Dale, Sandrine Boyault, Birgit Burkhardt, Adam P. Butler, Carlos Caldas, Helen R. Davies, Christine Desmedt, Roland Eils, Jórunn Erla Eyfjörd, John A. Foekens, Mel GreavesFumie Hosoda, Barbara Hutter, Tomislav Ilicic, Sandrine Imbeaud, Marcin Imielinski, Natalie Jäger, David T. W. Jones, David Jones, Stian Knappskog, Marcel Kool, Sunil R. Lakhani, Carlos López-Otín, Sancha Martin, Nikhil C Munshi, Hiromi Nakamura, Paul A. Northcott, Marina Pajic, Elli Papaemmanuil, Angelo Paradiso, John V. Pearson, Xose S. Puente, Keiran Raine, Manasa Ramakrishna, Andrea L. Richardson, Julia Richter, Philip Rosenstiel, Matthias Schlesner, Ton N. Schumacher, Paul N. Span, Jon W. Teague, Yasushi Totoki, Andrew N. J. Tutt, Rafael Valdés-Mas, Marit M. van Buuren, Laura van 't Veer, Anne Vincent-Salomon, Nicola Waddell, Lucy R. Yates, Australian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, ICGC PedBrain, Jessica Zucman-Rossi, P. Andrew Futreal, Ultan McDermott, Peter Lichter, Matthew Meyerson, Sean M. Grimmond, Reiner Siebert, Elías Campo, Tatsuhiro Shibata, Stefan M. Pfister, Peter J. Campbell, Michael R. Stratton

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

6275 Citations (Scopus)

Abstract

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational
processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC
family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

Original language	English
Pages (from-to)	415—421
Number of pages	11
Journal	Nature
Volume	500
Issue number	7463
DOIs	https://doi.org/10.1038/nature12477
Publication status	Published - 1 Aug 2013

Bibliographical note

A Corrigendum exists for this article and can be found in Nature (2013) Vol 502 p. 258 at doi: 10.1038/nature12666

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10.1038/nature12477

http://europepmc.org/articles/PMC3776390

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Alexandrov, L. B., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., Bignell, G. R., Bolli, N., Borg, A., Børresen-Dale, A-L., Boyault, S., Burkhardt, B., Butler, A. P., Caldas, C., Davies, H. R., Desmedt, C., Eils, R., Eyfjörd, J. E., Foekens, J. A., ... Stratton, M. R. (2013). Signatures of mutational processes in human cancer. Nature, 500(7463), 415—421. https://doi.org/10.1038/nature12477

Alexandrov, Ludmil B. ; Nik-Zainal, Serena ; Wedge, David C. ; Aparicio, Samuel A. J. R. ; Behjati, Sam ; Biankin, Andrew V. ; Bignell, Graham R. ; Bolli, Niccolò ; Borg, Ake ; Børresen-Dale, Anne-Lise ; Boyault, Sandrine ; Burkhardt, Birgit ; Butler, Adam P. ; Caldas, Carlos ; Davies, Helen R. ; Desmedt, Christine ; Eils, Roland ; Eyfjörd, Jórunn Erla ; Foekens, John A. ; Greaves, Mel ; Hosoda, Fumie ; Hutter, Barbara ; Ilicic, Tomislav ; Imbeaud, Sandrine ; Imielinski, Marcin ; Jäger, Natalie ; Jones, David T. W. ; Jones, David ; Knappskog, Stian ; Kool, Marcel ; Lakhani, Sunil R. ; López-Otín, Carlos ; Martin, Sancha ; Munshi, Nikhil C ; Nakamura, Hiromi ; Northcott, Paul A. ; Pajic, Marina ; Papaemmanuil, Elli ; Paradiso, Angelo ; Pearson, John V. ; Puente, Xose S. ; Raine, Keiran ; Ramakrishna, Manasa ; Richardson, Andrea L. ; Richter, Julia ; Rosenstiel, Philip ; Schlesner, Matthias ; Schumacher, Ton N. ; Span, Paul N. ; Teague, Jon W. ; Totoki, Yasushi ; Tutt, Andrew N. J. ; Valdés-Mas, Rafael ; van Buuren, Marit M. ; van 't Veer, Laura ; Vincent-Salomon, Anne ; Waddell, Nicola ; Yates, Lucy R. ; Australian Pancreatic Cancer Genome Initiative ; ICGC Breast Cancer Consortium ; ICGC MMML-Seq Consortium ; ICGC PedBrain ; Zucman-Rossi, Jessica ; Futreal, P. Andrew ; McDermott, Ultan ; Lichter, Peter ; Meyerson, Matthew ; Grimmond, Sean M. ; Siebert, Reiner ; Campo, Elías ; Shibata, Tatsuhiro ; Pfister, Stefan M. ; Campbell, Peter J. ; Stratton, Michael R. / Signatures of mutational processes in human cancer. In: Nature. 2013 ; Vol. 500, No. 7463. pp. 415—421.

@article{441a34d6cd7943258cc757f7c6fc117c,

title = "Signatures of mutational processes in human cancer",

abstract = "All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutationalprocesses that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBECfamily of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, {\textquoteleft}kataegis{\textquoteright}, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.",

author = "Alexandrov, {Ludmil B.} and Serena Nik-Zainal and Wedge, {David C.} and Aparicio, {Samuel A. J. R.} and Sam Behjati and Biankin, {Andrew V.} and Bignell, {Graham R.} and Niccol{\`o} Bolli and Ake Borg and Anne-Lise B{\o}rresen-Dale and Sandrine Boyault and Birgit Burkhardt and Butler, {Adam P.} and Carlos Caldas and Davies, {Helen R.} and Christine Desmedt and Roland Eils and Eyfj{\"o}rd, {J{\'o}runn Erla} and Foekens, {John A.} and Mel Greaves and Fumie Hosoda and Barbara Hutter and Tomislav Ilicic and Sandrine Imbeaud and Marcin Imielinski and Natalie J{\"a}ger and Jones, {David T. W.} and David Jones and Stian Knappskog and Marcel Kool and Lakhani, {Sunil R.} and Carlos L{\'o}pez-Ot{\'i}n and Sancha Martin and Munshi, {Nikhil C} and Hiromi Nakamura and Northcott, {Paul A.} and Marina Pajic and Elli Papaemmanuil and Angelo Paradiso and Pearson, {John V.} and Puente, {Xose S.} and Keiran Raine and Manasa Ramakrishna and Richardson, {Andrea L.} and Julia Richter and Philip Rosenstiel and Matthias Schlesner and Schumacher, {Ton N.} and Span, {Paul N.} and Teague, {Jon W.} and Yasushi Totoki and Tutt, {Andrew N. J.} and Rafael Vald{\'e}s-Mas and {van Buuren}, {Marit M.} and {van 't Veer}, Laura and Anne Vincent-Salomon and Nicola Waddell and Yates, {Lucy R.} and {Australian Pancreatic Cancer Genome Initiative} and Vincent Lam and {ICGC Breast Cancer Consortium} and {ICGC MMML-Seq Consortium} and {ICGC PedBrain} and Jessica Zucman-Rossi and Futreal, {P. Andrew} and Ultan McDermott and Peter Lichter and Matthew Meyerson and Grimmond, {Sean M.} and Reiner Siebert and El{\'i}as Campo and Tatsuhiro Shibata and Pfister, {Stefan M.} and Campbell, {Peter J.} and Stratton, {Michael R.}",

note = "A Corrigendum exists for this article and can be found in Nature (2013) Vol 502 p. 258 at doi: 10.1038/nature12666",

year = "2013",

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day = "1",

doi = "10.1038/nature12477",

language = "English",

volume = "500",

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journal = "Nature",

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Alexandrov, LB, Nik-Zainal, S, Wedge, DC, Aparicio, SAJR, Behjati, S, Biankin, AV, Bignell, GR, Bolli, N, Borg, A, Børresen-Dale, A-L, Boyault, S, Burkhardt, B, Butler, AP, Caldas, C, Davies, HR, Desmedt, C, Eils, R, Eyfjörd, JE, Foekens, JA, Greaves, M, Hosoda, F, Hutter, B, Ilicic, T, Imbeaud, S, Imielinski, M, Jäger, N, Jones, DTW, Jones, D, Knappskog, S, Kool, M, Lakhani, SR, López-Otín, C, Martin, S, Munshi, NC, Nakamura, H, Northcott, PA, Pajic, M, Papaemmanuil, E, Paradiso, A, Pearson, JV, Puente, XS, Raine, K, Ramakrishna, M, Richardson, AL, Richter, J, Rosenstiel, P, Schlesner, M, Schumacher, TN, Span, PN, Teague, JW, Totoki, Y, Tutt, ANJ, Valdés-Mas, R, van Buuren, MM, van 't Veer, L, Vincent-Salomon, A, Waddell, N, Yates, LR, Australian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, ICGC PedBrain, Zucman-Rossi, J, Futreal, PA, McDermott, U, Lichter, P, Meyerson, M, Grimmond, SM, Siebert, R, Campo, E, Shibata, T, Pfister, SM, Campbell, PJ & Stratton, MR 2013, 'Signatures of mutational processes in human cancer', Nature, vol. 500, no. 7463, pp. 415—421. https://doi.org/10.1038/nature12477

Signatures of mutational processes in human cancer. / Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.; Aparicio, Samuel A. J. R.; Behjati, Sam; Biankin, Andrew V.; Bignell, Graham R.; Bolli, Niccolò; Borg, Ake; Børresen-Dale, Anne-Lise; Boyault, Sandrine; Burkhardt, Birgit; Butler, Adam P.; Caldas, Carlos; Davies, Helen R.; Desmedt, Christine; Eils, Roland; Eyfjörd, Jórunn Erla; Foekens, John A.; Greaves, Mel; Hosoda, Fumie; Hutter, Barbara; Ilicic, Tomislav; Imbeaud, Sandrine; Imielinski, Marcin; Jäger, Natalie; Jones, David T. W.; Jones, David; Knappskog, Stian; Kool, Marcel; Lakhani, Sunil R.; López-Otín, Carlos; Martin, Sancha; Munshi, Nikhil C; Nakamura, Hiromi; Northcott, Paul A.; Pajic, Marina; Papaemmanuil, Elli; Paradiso, Angelo; Pearson, John V.; Puente, Xose S.; Raine, Keiran; Ramakrishna, Manasa; Richardson, Andrea L.; Richter, Julia; Rosenstiel, Philip; Schlesner, Matthias; Schumacher, Ton N.; Span, Paul N.; Teague, Jon W.; Totoki, Yasushi; Tutt, Andrew N. J.; Valdés-Mas, Rafael; van Buuren, Marit M.; van 't Veer, Laura; Vincent-Salomon, Anne; Waddell, Nicola; Yates, Lucy R.; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain; Zucman-Rossi, Jessica; Futreal, P. Andrew; McDermott, Ultan; Lichter, Peter; Meyerson, Matthew; Grimmond, Sean M.; Siebert, Reiner; Campo, Elías; Shibata, Tatsuhiro; Pfister, Stefan M.; Campbell, Peter J.; Stratton, Michael R.

In: Nature, Vol. 500, No. 7463, 01.08.2013, p. 415—421.

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

TY - JOUR

T1 - Signatures of mutational processes in human cancer

AU - Alexandrov, Ludmil B.

AU - Nik-Zainal, Serena

AU - Wedge, David C.

AU - Aparicio, Samuel A. J. R.

AU - Behjati, Sam

AU - Biankin, Andrew V.

AU - Bignell, Graham R.

AU - Bolli, Niccolò

AU - Borg, Ake

AU - Børresen-Dale, Anne-Lise

AU - Boyault, Sandrine

AU - Burkhardt, Birgit

AU - Butler, Adam P.

AU - Caldas, Carlos

AU - Davies, Helen R.

AU - Desmedt, Christine

AU - Eils, Roland

AU - Eyfjörd, Jórunn Erla

AU - Foekens, John A.

AU - Greaves, Mel

AU - Hosoda, Fumie

AU - Hutter, Barbara

AU - Ilicic, Tomislav

AU - Imbeaud, Sandrine

AU - Imielinski, Marcin

AU - Jäger, Natalie

AU - Jones, David T. W.

AU - Jones, David

AU - Knappskog, Stian

AU - Kool, Marcel

AU - Lakhani, Sunil R.

AU - López-Otín, Carlos

AU - Martin, Sancha

AU - Munshi, Nikhil C

AU - Nakamura, Hiromi

AU - Northcott, Paul A.

AU - Pajic, Marina

AU - Papaemmanuil, Elli

AU - Paradiso, Angelo

AU - Pearson, John V.

AU - Puente, Xose S.

AU - Raine, Keiran

AU - Ramakrishna, Manasa

AU - Richardson, Andrea L.

AU - Richter, Julia

AU - Rosenstiel, Philip

AU - Schlesner, Matthias

AU - Schumacher, Ton N.

AU - Span, Paul N.

AU - Teague, Jon W.

AU - Totoki, Yasushi

AU - Tutt, Andrew N. J.

AU - Valdés-Mas, Rafael

AU - van Buuren, Marit M.

AU - van 't Veer, Laura

AU - Vincent-Salomon, Anne

AU - Waddell, Nicola

AU - Yates, Lucy R.

AU - Australian Pancreatic Cancer Genome Initiative

AU - Lam, Vincent

AU - ICGC Breast Cancer Consortium

AU - ICGC MMML-Seq Consortium

AU - ICGC PedBrain

AU - Zucman-Rossi, Jessica

AU - Futreal, P. Andrew

AU - McDermott, Ultan

AU - Lichter, Peter

AU - Meyerson, Matthew

AU - Grimmond, Sean M.

AU - Siebert, Reiner

AU - Campo, Elías

AU - Shibata, Tatsuhiro

AU - Pfister, Stefan M.

AU - Campbell, Peter J.

AU - Stratton, Michael R.

N1 - A Corrigendum exists for this article and can be found in Nature (2013) Vol 502 p. 258 at doi: 10.1038/nature12666

PY - 2013/8/1

Y1 - 2013/8/1

N2 - All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutationalprocesses that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBECfamily of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

AB - All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutationalprocesses that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBECfamily of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

U2 - 10.1038/nature12477

DO - 10.1038/nature12477

M3 - Article

C2 - 23945592

VL - 500

SP - 415—421

JO - Nature

JF - Nature

SN - 1476-4687

IS - 7463

ER -

Signatures of mutational processes in human cancer

Abstract

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