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, Alexander Claviez, Andreas Rosenwald, Andreas Rosenwald, Arndt Borkhardt, Benedikt Brors, Bernhard Radlwimmer, Chris Lawerenz, Cristina Lopez, David Langenberger, Dennis Karsch, Dido Lenze, Dieter Kube, Ellen Leich, Gesine Richter, Jan Korbel, Jessica Hoell, Jürgen Eils, Kebriah Hezaveh, Lorenz Trümper, Maciej Rosolowski, Marc Weniger, Marius Rohde, Markus Kreuz, Markus Loeffler, Markus Schilhabel, Martin Dreyling, Martin-Leo Hansmann, Michael Hummel, Monika Szczepanowski, Ole Ammerpohl, Peter F Stadler, Peter Möller, Ralf Küppers, Siegfried Haas, Sonja Eberth, Stefan Schreiber, Stephan H Bernhart, Steve Hoffmann, Sylwester Radomski, Ulrike Kostezka, Wolfram Klapper, Christos Sotiriou, Denis Larsimont, Delphine Vincent, Marion Maetens, Odette Mariani, Anieta M Sieuwerts, John W M Martens, Jon G Jonasson, Isabelle Treilleux, Emilie Thomas, Gaëtan Mac Grogan, Cécile Mannina, Laurent Arnould, Laura Burillier, Jean-Louis Merlin, Magali Lefebvre, Frédéric Bibeau, Blandine Massemin, Frédérique Penault-Llorca, Qian Lopez, Marie-Christine Mathieu, Per Eystein Lonning, Margrete Schlooz-Vries, Jolien Tol, Hanneke van Laarhoven, Fred Sweep, Peter Bult, 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, Alexander Claviez, Andreas Rosenwald, Andreas Rosenwald, Arndt Borkhardt, Benedikt Brors, Bernhard Radlwimmer, Chris Lawerenz, Cristina Lopez, David Langenberger, Dennis Karsch, Dido Lenze, Dieter Kube, Ellen Leich, Gesine Richter, Jan Korbel, Jessica Hoell, Jürgen Eils, Kebriah Hezaveh, Lorenz Trümper, Maciej Rosolowski, Marc Weniger, Marius Rohde, Markus Kreuz, Markus Loeffler, Markus Schilhabel, Martin Dreyling, Martin-Leo Hansmann, Michael Hummel, Monika Szczepanowski, Ole Ammerpohl, Peter F Stadler, Peter Möller, Ralf Küppers, Siegfried Haas, Sonja Eberth, Stefan Schreiber, Stephan H Bernhart, Steve Hoffmann, Sylwester Radomski, Ulrike Kostezka, Wolfram Klapper, Christos Sotiriou, Denis Larsimont, Delphine Vincent, Marion Maetens, Odette Mariani, Anieta M Sieuwerts, John W M Martens, Jon G Jonasson, Isabelle Treilleux, Emilie Thomas, Gaëtan Mac Grogan, Cécile Mannina, Laurent Arnould, Laura Burillier, Jean-Louis Merlin, Magali Lefebvre, Frédéric Bibeau, Blandine Massemin, Frédérique Penault-Llorca, Qian Lopez, Marie-Christine Mathieu, Per Eystein Lonning, Margrete Schlooz-Vries, Jolien Tol, Hanneke van Laarhoven, Fred Sweep, Peter Bult
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.
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References
- Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458:719–724. doi:10.1038/nature07943.
- Pfeifer GP. Environmental exposures and mutational patterns of cancer genomes. Genome medicine. 2010;2:54.
- Pena-Diaz J, et al. Noncanonical mismatch repair as a source of genomic instability in human cells. Molecular cell. 2012;47:669–680.
- Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008. doi:10.1101/cshperspect.a001008.
- Alexandrov LB, Nik-Zainal S, Wedge DC, Campbell PJ, Stratton MR. Deciphering signatures of mutational processes operative in human cancer. Cell reports. 2013;3:246–259. doi:10.1016/j.celrep.2012.12.008.
- Nik-Zainal S, et al. Mutational Processes Molding the Genomes of 21 Breast Cancers. Cell. 2012;149:979–993.
- Nik-Zainal S, et al. The life history of 21 breast cancers. Cell. 2012;149:994–1007. doi:10.1016/j.cell.2012.04.023.
- Hudson TJ, et al. International network of cancer genome projects. Nature. 2010;464:993–998. doi:10.1038/nature08987.
- Pfeifer GP. Mutagenesis at methylated CpG sequences. Curr Top Microbiol Immunol. 2006;301:259–281.
- Welch JS, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150:264–278. doi:10.1016/j.cell.2012.06.023.
- Di Noia JM, Neuberger MS. Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem. 2007;76:1–22. doi:10.1146/annurev.biochem.76.061705.090740.
- Hanawalt PC, Spivak G. Transcription-coupled DNA repair: two decades of progress and surprises. Nat Rev Mol Cell Biol. 2008;9:958–970. doi:10.1038/nrm2549.
- Pfeifer GP, et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 2002;21:7435–7451. doi:10.1038/sj.onc.1205803.
- Pfeifer GP, You YH, Besaratinia A. Mutations induced by ultraviolet light. Mutat Res. 2005;571:19–31. doi:10.1016/j.mrfmmm.2004.06.057.
- Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073–2087. e2073. doi:10.1053/j.gastro.2009.12.064.
- Thompson LH. Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography. Mutat Res. 2012;751:158–246. doi:10.1016/j.mrrev.2012.06.002.
- Hunter C, et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer research. 2006;66:3987–3991.
- Tomita-Mitchell A, et al. Mismatch repair deficient human cells: spontaneous and MNNG-induced mutational spectra in the HPRT gene. Mutat Res. 2000;450:125–138.
- Taylor BJM, et al. DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. eLife. 2013;2:e00534.
- Burns MB, et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature. 2013;494:366–370. doi:10.1038/nature11881.
- Harris RS, Petersen-Mahrt SK, Neuberger MS. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Molecular cell. 2002;10:1247–1253.
- Koito A, Ikeda T. Intrinsic immunity against retrotransposons by APOBEC cytidine deaminases. Front Microbiol. 2013;4:28. doi:10.3389/fmicb.2013.00028.
- Puente XS, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–105. doi:10.1038/nature10113.
- Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. doi:10.1038/nature11252.
- Cancer Genome Atlas Research, N. et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73. doi:10.1038/nature12113.
- Lawrence MS, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013 doi:10.1038/nature12213.
- Holmfeldt L, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nature genetics. 2013;45:242–252. doi:10.1038/ng.2532.
- Zhang J, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481:157–163. doi:10.1038/nature10725.
- De Keersmaecker K, et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nature genetics. 2013;45:186–190. doi:10.1038/ng.2508.
- Ding L, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–510. doi:10.1038/nature10738.
- Stephens PJ, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486:400–404. doi:10.1038/nature11017.
- Quesada V, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nature genetics. 2012;44:47–52. doi:10.1038/ng.1032.
- Seshagiri S, et al. Recurrent R-spondin fusions in colon cancer. Nature. 2012;488:660–664. doi:10.1038/nature11282.
- Dulak AM, et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nature genetics. 2013 doi:10.1038/ng.2591.
- Agrawal N, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333:1154–1157. doi:10.1126/science.1206923.
- Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333:1157–1160. doi:10.1126/science.1208130.
- Guo G, et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nature genetics. 2012;44:17–19. doi:10.1038/ng.1014.
- Pena-Llopis S, et al. BAP1 loss defines a new class of renal cell carcinoma. Nature genetics. 2012;44:751–759. doi:10.1038/ng.2323.
- Ding L, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069–1075. doi:10.1038/nature07423.
- Seo JS, et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome research. 2012;22:2109–2119. doi:10.1101/gr.145144.112.
- Imielinski M, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150:1107–1120. doi:10.1016/j.cell.2012.08.029.
- Love C, et al. The genetic landscape of mutations in Burkitt lymphoma. Nature genetics. 2012;44:1321–1325. doi:10.1038/ng.2468.
- Zhang J, et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nature genetics. 2013 doi:10.1038/ng.2611.
- Morin RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303. doi:10.1038/nature10351.
- Jiao Y, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–1203. doi:10.1126/science.1200609.
- Pugh TJ, et al. The genetic landscape of high-risk neuroblastoma. Nature genetics. 2013;45:279–284. doi:10.1038/ng.2529.
- Jones S, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. 2010;330:228–231. doi:10.1126/science.1196333.
- Wu J, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proceedings of the National Academy of Sciences of the United States of America. 2011;108:21188–21193. doi:10.1073/pnas.1118046108.
- Sausen M, et al. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nature genetics. 2013;45:12–17. doi:10.1038/ng.2493.
- Berger MF, et al. The genomic complexity of primary human prostate cancer. Nature. 2011;470:214–220. doi:10.1038/nature09744.
- Grasso CS, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–243. doi:10.1038/nature11125.
- Barbieri CE, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature genetics. 2012;44:685–689. doi:10.1038/ng.2279.
- Rudin CM, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature genetics. 2012;44:1111–1116. doi:10.1038/ng.2405.
- Peifer M, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature genetics. 2012;44:1104–1110. doi:10.1038/ng.2396.
- Stark MS, et al. Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nature genetics. 2012;44:165–169. doi:10.1038/ng.1041.
- Berger MF, et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012;485:502–506. doi:10.1038/nature11071.
- Hodis E, et al. A landscape of driver mutations in melanoma. Cell. 2012;150:251–263. doi:10.1016/j.cell.2012.06.024.
- Zang ZJ, et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nature genetics. 2012;44:570–574. doi:10.1038/ng.2246.
- Wang K, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nature genetics. 2011;43:1219–1223. doi:10.1038/ng.982.
- Sherry ST, et al. dbSNP: the NCBI database of genetic variation. Nucleic acids research. 2001;29:308–311.
- Abecasis GR, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65. doi:10.1038/nature11632.
- Fu W, et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 2013;493:216–220. doi:10.1038/nature11690.
- Baumbusch LO, et al. Comparison of the Agilent, ROMA/NimbleGen and Illumina platforms for classification of copy number alterations in human breast tumors. BMC Genomics. 2008;9:379.
- Pickrell JK, Gaffney DJ, Gilad Y, Pritchard JK. False positive peaks in ChIP-seq and other sequencing-based functional assays caused by unannotated high copy number regions. Bioinformatics. 2011;27:2144–2146.
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