Mutational signatures: the patterns of somatic mutations hidden in cancer genomes

Ludmil B Alexandrov, Michael R Stratton, Ludmil B Alexandrov, Michael R Stratton

Abstract

All cancers originate from a single cell that starts to behave abnormally due to the acquired somatic mutations in its genome. Until recently, the knowledge of the mutational processes that cause these somatic mutations has been very limited. Recent advances in sequencing technologies and the development of novel mathematical approaches have allowed deciphering the patterns of somatic mutations caused by different mutational processes. Here, we summarize our current understanding of mutational patterns and mutational signatures in light of both the somatic cell paradigm of cancer research and the recent developments in the field of cancer genomics.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Mutational processes operative in a cancer. This simulated example illustrates four distinct mutational processes with variable strengths operative at different times throughout the lifetime of the patient. Each of these processes has a unique mutational signature exemplified by the six classes of somatic substitutions. At the beginning, all mutations in the cell (from which the cancer was eventually developed) were due to the activity of the endogenous mutational process 1. As time progresses, the other mutational process get activated and the spectrum of the cell continues to change. Note that the final sequenced cancer genome does not resemble any of the operative mutational signatures.

References

    1. Watson J.D., Crick F.H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953;171:37–738.
    1. Rusch H.P., Baumann C.A. Tumor production in mice with ultraviolet irradiation. Am J Cancer. 1939;35:55–62.
    1. Blum H.F. On the mechanism of cancer induction by ultraviolet radiation. J Natl Cancer Inst. 1950;11:463–495.
    1. Witkin E.M. Ultraviolet-induced mutation and DNA repair. Annu Rev Microbiol. 1969;23:487–514.

    2. This review summarizes the very early effors to understand UV-light induced DNA mutations.

    1. Howard B.D., Tessman I. Identification of the altered bases in mutated single-stranded DNA. II. In vivo mutagenesis by 5-bromodeoxyuridine and 2-aminopurine. J Mol Biol. 1964;9:364–371.
    1. Setlow R.B., Carrier W.L. Pyrimidine dimers in ultraviolet-irradiated DNA's. J Mol Biol. 1966;17:237–254.
    1. Sanger F., Nicklen S., Coulson A.R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA. 1977;74:5463–5467.
    1. Brash D.E., Rudolph J.A., Simon J.A., Lin A., McKenna G.J., Baden H.P., Halperin A.J., Ponten J. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA. 1991;88:10124–10128.

    2. This article provides one of the early evidences that UV light leaves a specific mutational imprint on the DNA of a cancer cell, viz., C > T substitutions at dipyrimidines. This imprint is consistent with the one observed in previous in vitro experiments.

    1. Ozturk M. P53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet. 1991;338:1356–1359.

    2. This article provides one of the early evidences that aflatoxin leaves a specific mutational imprint on the DNA of a cancer cell, viz., C > A substitutions. This imprint is consistent with the one observed in previous experiments.

    1. Vogelstein B., Kinzler K.W. Carcinogens leave fingerprints. Nature. 1992;355:209–210.
    1. Greenblatt M.S., Bennett W.P., Hollstein M., Harris C.C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–4878.

    2. This very detailed review summarizes the studies analyzing TP53 mutational spectra and their relationship with epidemiology.

    1. Hollstein M., Sidransky D., Vogelstein B., Harris C.C. P53 mutations in human cancers. Science. 1991;253:49–53.
    1. Hollstein M., Hergenhahn M., Yang Q., Bartsch H., Wang Z.Q., Hainaut P. New approaches to understanding p53 gene tumor mutation spectra. Mutat Res. 1999;431:199–209.
    1. Capella G., Cronauer-Mitra S., Pienado M.A., Perucho M. Frequency and spectrum of mutations at codons 12 and 13 of the c-k-ras gene in human tumors. Environ Health Perspect. 1991;93:125–131.
    1. Rodin S.N., Rodin A.S. Origins and selection of p53 mutations in lung carcinogenesis. Semin Cancer Biol. 2005;15:103–112.
    1. Wogan G.N. Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res. 1992;52(7 Suppl):2114s–2118s.
    1. Hainaut P., Olivier M., Pfeifer G.P. Tp53 mutation spectrum in lung cancers and mutagenic signature of components of tobacco smoke: lessons from the iarc tp53 mutation database. Mutagenesis. 2001;16:551–553. [author reply 555–6]
    1. Cariello N.F., Cui L., Beroud C., Soussi T. Database and software for the analysis of mutations in the human p53 gene. Cancer Res. 1994;54:4454–4460.
    1. Alexandrov L.B., Nik-Zainal S., Wedge D.C., Aparicio S.A., Behjati S., Biankin A.V., Bignell G.R., Bolli N., Borg A., Borresen-Dale A.L., Boyault S. Signatures of mutational processes in human cancer. Nature. 2013;500:415–421.

    2. This study provides the first comprehensive map of the signatures of mutational processes across 30 different types of human cancer derived from 7 042 patients

    1. Alexandrov L.B., Nik-Zainal S., Wedge D.C., Campbell P.J., Stratton M.R. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 2013;3:246–259.

    2. This study provides a mathematical approach and computational framework that allow identifying mutational signatures from next generation sequencing data.

    1. Stratton M.R. Exploring the genomes of cancer cells: progress and promise. Science. 2011;331:1553–1558.
    1. Stratton M.R., Campbell P.J., Futreal P.A. The cancer genome. Nature. 2009;458:719–724.
    1. Stephens P., Edkins S., Davies H., Greenman C., Cox C., Hunter C., Bignell G., Teague J., Smith R., Stevens C., O’Meara S. A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat Genet. 2005;37:590–592.
    1. Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446:153–158.
    1. Rubin A.F., Green P. Mutation patterns in cancer genomes. Proc Natl Acad Sci USA. 2009;106:21766–21770.
    1. International Cancer Genome C., Hudson T.J., Anderson W., Artez A., Barker A.D., Bell C., Bernabe R.R., Bhan M.K., Calvo F., Eerola I., Gerhard D.S. International network of cancer genome projects. Nature. 2010;464:993–998.
    1. Pleasance E.D., Cheetham R.K., Stephens P.J., McBride D.J., Humphray S.J., Greenman C.D., Varela I., Lin M.L., Ordonez G.R., Bignell G.R., Ye K. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463:191–196.

    2. The Pleasance et al. back-to-back articles in Nature demonstrate the value of whole genome sequencing for evaluating signatures of mutational processes by providing greater resolution and mechanistic insight.

    1. Pleasance E.D., Stephens P.J., O’Meara S., McBride D.J., Meynert A., Jones D., Lin M.L., Beare D., Lau K.W., Greenman C., Varela I. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2010;463:184–190.

    2. The Pleasance et al. back-to-back articles in Nature demonstrate the value of whole genome sequencing for evaluating signatures of mutational processes by providing greater resolution and mechanistic insight.

    1. De Keersmaecker K., Atak Z.K., Li N., Vicente C., Patchett S., Girardi T., Gianfelici V., Geerdens E., Clappier E., Porcu M., Lahortiga I. Exome sequencing identifies mutation in cnot3 and ribosomal genes rpl5 and rpl10 in t-cell acute lymphoblastic leukemia. Nat Genet. 2013;45:186–190.
    1. Holmfeldt L., Wei L., Diaz-Flores E., Walsh M., Zhang J., Ding L., Payne-Turner D., Churchman M., Andersson A., Chen S.C., McCastlain K. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45:242–252.
    1. Zhang J., Ding L., Holmfeldt L., Wu G., Heatley S.L., Payne-Turner D., Easton J., Chen X., Wang J., Rusch M., Lu C. The genetic basis of early t-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481:157–163.
    1. Ding L., Ley T.J., Larson D.E., Miller C.A., Koboldt D.C., Welch J.S., Ritchey J.K., Young M.A., Lamprecht T., McLellan M.D., McMichael J.F. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–510.
    1. Nik-Zainal S., Alexandrov L.B., Wedge D.C., Van Loo P., Greenman C.D., Raine K., Jones D., Hinton J., Marshall J., Stebbings L.A., Menzies A. Mutational processes molding the genomes of 21 breast cancers. Cell. 2012;149:979–993.

    2. This study demostrates that mutplie mutational processes are operative in 21 breast cancer sample. It also demonstrates the existance of localized somatic hypermutation, termed kataegis, for the first time.

    1. Shah S.P., Roth A., Goya R., Oloumi A., Ha G., Zhao Y., Turashvili G., Ding J., Tse K., Haffari G., Bashashati A. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486:395–399.
    1. Stephens P.J., Tarpey P.S., Davies H., Van Loo P., Greenman C., Wedge D.C., Nik-Zainal S., Martin S., Varela I., Bignell G.R., Yates L.R. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486:400–404.
    1. Puente X.S., Pinyol M., Quesada V., Conde L., Ordonez G.R., Villamor N., Escaramis G., Jares P., Bea S., Gonzalez-Diaz M., Bassaganyas L. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–105.
    1. Quesada V., Conde L., Villamor N., Ordonez G.R., Jares P., Bassaganyas L., Ramsay A.J., Bea S., Pinyol M., Martinez-Trillos A., Lopez-Guerra M. Exome sequencing identifies recurrent mutations of the splicing factor sf3b1 gene in chronic lymphocytic leukemia. Nat Genet. 2012;44:47–52.
    1. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337.
    1. Seshagiri S., Stawiski E.W., Durinck S., Modrusan Z., Storm E.E., Conboy C.B., Chaudhuri S., Guan Y., Janakiraman V., Jaiswal B.S., Guillory J. Recurrent r-spondin fusions in colon cancer. Nature. 2012;488:660–664.
    1. Dulak A.M., Stojanov P., Peng S., Lawrence M.S., Fox C., Stewart C., Bandla S., Imamura Y., Schumacher S.E., Shefler E., McKenna A. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet. 2013;45:478–486.
    1. Parsons D.W., Jones S., Zhang X., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H., Siu I.M., Gallia G.L., Olivi A. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–1812.
    1. Agrawal N., Frederick M.J., Pickering C.R., Bettegowda C., Chang K., Li R.J., Fakhry C., Xie T.X., Zhang J., Wang J., Zhang N. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in notch1. Science. 2011;333:1154–1157.
    1. Stransky N., Egloff A.M., Tward A.D., Kostic A.D., Cibulskis K., Sivachenko A., Kryukov G.V., Lawrence M.S., Sougnez C., McKenna A., Shefler E. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333:1157–1160.
    1. Cancer Genome Atlas Research Network Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–49.
    1. Guo G., Gui Y., Gao S., Tang A., Hu X., Huang Y., Jia W., Li Z., He M., Sun L., Song P. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet. 2012;44:17–19.
    1. Pena-Llopis S., Vega-Rubin-de-Celis S., Liao A., Leng N., Pavia-Jimenez A., Wang S., Yamasaki T., Zhrebker L., Sivanand S., Spence P., Kinch L. Bap1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012;44:751–759.
    1. Kan Z., Zheng H., Liu X., Li S., Barber T.D., Gong Z., Gao H., Hao K., Willard M.D., Xu J., Hauptschein R. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013;23:1422–1433.
    1. Fujimoto A., Totoki Y., Abe T., Boroevich K.A., Hosoda F., Nguyen H.H., Aoki M., Hosono N., Kubo M., Miya F., Arai Y. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012;44:760–764.
    1. Seo J.S., Ju Y.S., Lee W.C., Shin J.Y., Lee J.K., Bleazard T., Lee J., Jung Y.J., Kim J.O., Shin J.Y., Yu S.B. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res. 2012;22:2109–2119.
    1. Imielinski M., Berger A.H., Hammerman P.S., Hernandez B., Pugh T.J., Hodis E., Cho J., Suh J., Capelletti M., Sivachenko A., Sougnez C. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150:1107–1120.
    1. Govindan R., Ding L., Griffith M., Subramanian J., Dees N.D., Kanchi K.L., Maher C.A., Fulton R., Fulton L., Wallis J., Chen K. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150:1121–1134.
    1. Ding L., Getz G., Wheeler D.A., Mardis E.R., McLellan M.D., Cibulskis K., Sougnez C., Greulich H., Muzny D.M., Morgan M.B., Fulton L. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069–1075.
    1. Peifer M., Fernandez-Cuesta L., Sos M.L., George J., Seidel D., Kasper L.H., Plenker D., Leenders F., Sun R., Zander T., Menon R. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104–1110.
    1. Rudin C.M., Durinck S., Stawiski E.W., Poirier J.T., Modrusan Z., Shames D.S., Bergbower E.A., Guan Y., Shin J., Guillory J., Rivers C.S. Comprehensive genomic analysis identifies sox2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012;44:1111–1116.
    1. Love C., Sun Z., Jima D., Li G., Zhang J., Miles R., Richards K.L., Dunphy C.H., Choi W.W., Srivastava G., Lugar P.L. The genetic landscape of mutations in burkitt lymphoma. Nat Genet. 2012;44:1321–1325.
    1. Morin R.D., Mendez-Lago M., Mungall A.J., Goya R., Mungall K.L., Corbett R.D., Johnson N.A., Severson T.M., Chiu R., Field M., Jackman S. Frequent mutation of histone-modifying genes in non-hodgkin lymphoma. Nature. 2011;476:298–303.
    1. Huang F.W., Hodis E., Xu M.J., Kryukov G.V., Chin L., Garraway L.A. Highly recurrent tert promoter mutations in human melanoma. Science. 2013;339:957–959.
    1. Stark M.S., Woods S.L., Gartside M.G., Bonazzi V.F., Dutton-Regester K., Aoude L.G., Chow D., Sereduk C., Niemi N.M., Tang N., Ellis J.J. Frequent somatic mutations in map3k5 and map3k9 in metastatic melanoma identified by exome sequencing. Nat Genet. 2012;44:165–169.
    1. Berger M.F., Hodis E., Heffernan T.P., Deribe Y.L., Lawrence M.S., Protopopov A., Ivanova E., Watson I.R., Nickerson E., Ghosh P., Zhang H. Melanoma genome sequencing reveals frequent prex2 mutations. Nature. 2012;485:502–506.
    1. Hodis E., Watson I.R., Kryukov G.V., Arold S.T., Imielinski M., Theurillat J.P., Nickerson E., Auclair D., Li L., Place C., Dicara D. A landscape of driver mutations in melanoma. Cell. 2012;150:251–263.
    1. Chapman M.A., Lawrence M.S., Keats J.J., Cibulskis K., Sougnez C., Schinzel A.C., Harview C.L., Brunet J.P., Ahmann G.J., Adli M., Anderson K.C. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–472.
    1. Jones S., Wang T.L., Shih Ie M., Mao T.L., Nakayama K., Roden R., Glas R., Slamon D., Diaz L.A., Jr., Vogelstein B., Kinzler K.W. Frequent mutations of chromatin remodeling gene arid1a in ovarian clear cell carcinoma. Science. 2010;330:228–231.
    1. Jiao Y., Shi C., Edil B.H., de Wilde R.F., Klimstra D.S., Maitra A., Schulick R.D., Tang L.H., Wolfgang C.L., Choti M.A., Velculescu V.E. Daxx/atrx, men1, and mtor pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–1203.
    1. Wu J., Jiao Y., Dal Molin M., Maitra A., de Wilde R.F., Wood L.D., Eshleman J.R., Goggins M.G., Wolfgang C.L., Canto M.I., Schulick R.D. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci USA. 2011;108:21188–21193.
    1. Baca S.C., Prandi D., Lawrence M.S., Mosquera J.M., Romanel A., Drier Y., Park K., Kitabayashi N., MacDonald T.Y., Ghandi M., Van Allen E. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–677.
    1. Grasso C.S., Wu Y.M., Robinson D.R., Cao X., Dhanasekaran S.M., Khan A.P., Quist M.J., Jing X., Lonigro R.J., Brenner J.C., Asangani I.A. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–243.
    1. Barbieri C.E., Baca S.C., Lawrence M.S., Demichelis F., Blattner M., Theurillat J.P., White T.A., Stojanov P., Van Allen E., Stransky N., Nickerson E. Exome sequencing identifies recurrent spop, foxa1 and med12 mutations in prostate cancer. Nat Genet. 2012;44:685–689.
    1. Berger M.F., Lawrence M.S., Demichelis F., Drier Y., Cibulskis K., Sivachenko A.Y., Sboner A., Esgueva R., Pflueger D., Sougnez C., Onofrio R. The genomic complexity of primary human prostate cancer. Nature. 2011;470:214–220.
    1. Zang Z.J., Cutcutache I., Poon S.L., Zhang S.L., McPherson J.R., Tao J., Rajasegaran V., Heng H.L., Deng N., Gan A., Lim K.H. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet. 2012;44:570–574.
    1. Wang K., Kan J., Yuen S.T., Shi S.T., Chu K.M., Law S., Chan T.L., Kan Z., Chan A.S., Tsui W.Y., Lee S.P. Exome sequencing identifies frequent mutation of arid1a in molecular subtypes of gastric cancer. Nat Genet. 2011;43:1219–1223.
    1. Nagarajan N., Bertrand D., Hillmer A.M., Zang Z.J., Yao F., Jacques P.E., Teo A.S., Cutcutache I., Zhang Z., Lee W.H., Sia Y.Y. Whole-genome reconstruction and mutational signatures in gastric cancer. Genome Biol. 2012;13:R115.
    1. Cancer Genome Atlas Research Network, Kandoth C., Schultz N., Cherniack A.D., Akbani R., Liu Y., Shen H., Robertson A.G., Pashtan I., Shen R., Benz C.C. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.
    1. Robinson G., Parker M., Kranenburg T.A., Lu C., Chen X., Ding L., Phoenix T.N., Hedlund E., Wei L., Zhu X., Chalhoub N. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012;488:43–48.
    1. Rausch T., Jones D.T., Zapatka M., Stutz A.M., Zichner T., Weischenfeldt J., Jager N., Remke M., Shih D., Northcott P.A., Pfaff E. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with tp53 mutations. Cell. 2012;148:59–71.
    1. Pugh T.J., Weeraratne S.D., Archer T.C., Pomeranz Krummel D.A., Auclair D., Bochicchio J., Carneiro M.O., Carter S.L., Cibulskis K., Erlich R.L., Greulich H., et al Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012;488:106–110.
    1. Jones D.T., Jager N., Kool M., Zichner T., Hutter B., Sultan M., Cho Y.J., Pugh T.J., Hovestadt V., Stutz A.M., Rausch T. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488:100–105.
    1. Pugh T.J., Morozova O., Attiyeh E.F., Asgharzadeh S., Wei J.S., Auclair D., Carter S.L., Cibulskis K., Hanna M., Kiezun A., Kim J. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013;45:279–284.
    1. Sausen M., Leary R.J., Jones S., Wu J., Reynolds C.P., Liu X., Blackford A., Parmigiani G., Diaz L.A., Jr., Papadopoulos N., Vogelstein B. Integrated genomic analyses identify arid1a and arid1b alterations in the childhood cancer neuroblastoma. Nat Genet. 2013;45:12–17.
    1. Zhang J., Wu G., Miller C.P., Tatevossian R.G., Dalton J.D., Tang B., Orisme W., Punchihewa C., Parker M., Qaddoumi I., Boop F.A. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet. 2013;45:602–612.
    1. Spencer J., Dunn-Walters D.K. Hypermutation at a–t base pairs: the a nucleotide replacement spectrum is affected by adjacent nucleotides and there is no reverse complementarity of sequences flanking mutated a and t nucleotides. J Immunol. 2005;175:5170–5177.
    1. Hoang M.L., Chen C.H., Sidorenko V.S., He J., Dickman K.G., Yun B.H., Moriya M., Niknafs N., Douville C., Karchin R., Turesky R.J. Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci Transl Med. 2013;5:197ra102.
    1. Comon P. Elsevier; 2010. Handbook of blind source separation: independent component analysis and blind deconvolution.
    1. Lee D.D., Seung H.S. Learning the parts of objects by non-negative matrix factorization. Nature. 1999;401:788–791.
    1. Taylor B.J., Nik-Zainal S., Wu Y.L., Stebbings L.A., Raine K., Campbell P.J., Rada C., Stratton M.R., Neuberger M.S. DNA deaminases induce break-associated mutation showers with implication of apobec3b and 3a in breast cancer kataegis. eLife. 2013;2:e00534.
    1. Harris R.S., Petersen-Mahrt S.K., Neuberger M.S. Rna editing enzyme apobec1 and some of its homologs can act as DNA mutators. Mol Cell. 2002;10:1247–1253.
    1. Nik-Zainal S., Van Loo P., Wedge D.C., Alexandrov L.B., Greenman C.D., Lau K.W., Raine K., Jones D., Marshall J., Ramakrishna M., Shlien A. The life history of 21 breast cancers. Cell. 2012;149:994–1007.
    1. van Zeeland A.A., Vreeswijk M.P., de Gruijl F.R., van Kranen H.J., Vrieling H., Mullenders L.F. Transcription-coupled repair: impact on uv-induced mutagenesis in cultured rodent cells and mouse skin tumors. Mutat Res. 2005;577:170–178.

    2. This article explains the interplay between transcription-coupled repair and mutations induced by UV-light.

    1. Roberts S.A., Lawrence M.S., Klimczak L.J., Grimm S.A., Fargo D., Stojanov P., Kiezun A., Kryukov G.V., Carter S.L., Saksena G., Harris S. An apobec cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet. 2013;45:970–976.
    1. Burns M.B., Temiz N.A., Harris R.S. Evidence for apobec3b mutagenesis in multiple human cancers. Nat Genet. 2013;45:977–983.

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