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Mutational spectra of human cancer

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Abstract

The purpose of this review is to summarize the evidence that can be used to reconstruct the etiology of human cancers from mutations found in tumors. Mutational spectra of the tumor suppressor gene p53 (TP53) are tumor specific. In several cases, these mutational spectra can be linked to exogenous carcinogens, most notably for sunlight-associated skin cancers, tobacco-associated lung cancers, and aristolochic acid-related urothelial tumors. In the TP53 gene, methylated CpG dinucleotides are sequences selectively targeted by endogenous and exogenous mutagenic processes. Recent high-throughput sequencing efforts analyzing a large number of genes in cancer genomes have so far, for the most part, produced mutational spectra similar to those in TP53 but have unveiled a previously unrecognized common G to C transversion mutation signature at GpA dinucleotides in breast cancers and several other cancers. Unraveling the origin of these G to C mutations will be of importance for understanding cancer etiology.

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References

  • Albertini RJ (2001) HPRT mutations in humans: biomarkers for mechanistic studies. Mutat Res 489:1–16

    Article  PubMed  CAS  Google Scholar 

  • Arlt VM (2005) 3-Nitrobenzanthrone, a potential human cancer hazard in diesel exhaust and urban air pollution: a review of the evidence. Mutagenesis 20:399–410

    Article  PubMed  CAS  Google Scholar 

  • Arlt VM, Schmeiser HH, Pfeifer GP (2001) Sequence-specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR. Carcinogenesis 22:133–140

    Article  PubMed  CAS  Google Scholar 

  • Arlt VM, Stiborova M, Schmeiser HH (2002) Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 17:265–277

    Article  PubMed  CAS  Google Scholar 

  • Barbacid M (1987) ras genes. Annu Rev Biochem 56:779–827

    Article  PubMed  CAS  Google Scholar 

  • Besaratinia A, Pfeifer GP (2006) Investigating human cancer etiology by DNA lesion footprinting and mutagenicity analysis. Carcinogenesis 27:1526–1537

    Article  PubMed  CAS  Google Scholar 

  • Besaratinia A, Pfeifer GP (2008) Second-hand smoke and human lung cancer. Lancet Oncol 9:657–666

    Article  PubMed  CAS  Google Scholar 

  • Bodmer W (2008) Genetic instability is not a requirement for tumor development. Cancer Res 68:3558–3560 discussion 3560–3561

    Article  PubMed  CAS  Google Scholar 

  • Bos JL (1989) ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689

    PubMed  CAS  Google Scholar 

  • Carbone M, Klein G, Gruber J, Wong M (2004) Modern criteria to establish human cancer etiology. Cancer Res 64:5518–5524

    Article  PubMed  CAS  Google Scholar 

  • Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–444

    Article  PubMed  CAS  Google Scholar 

  • Chin L, Gray JW (2008) Translating insights from the cancer genome into clinical practice. Nature 452:553–563

    Article  PubMed  CAS  Google Scholar 

  • Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155

    Article  PubMed  CAS  Google Scholar 

  • Coulondre C, Miller JH, Farabaugh PJ, Gilbert W (1978) Molecular basis of base substitution hotspots in Escherichia coli. Nature 274:775–780

    Article  PubMed  CAS  Google Scholar 

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  PubMed  CAS  Google Scholar 

  • Denissenko MF, Pao A, Tang M-S, Pfeifer GP (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science 274:430–432

    Article  PubMed  CAS  Google Scholar 

  • Denissenko MF, Chen JX, Tang M-S, Pfeifer GP (1997) Cytosine methylation determines hot spots of DNA damage in the human P53 gene. Proc Natl Acad Sci USA 94:3893–3898

    Article  PubMed  CAS  Google Scholar 

  • Denissenko MF, Koudriakova TB, Smith L, O’Connor TR, Riggs AD, Pfeifer GP (1998) The P53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B1 adducts. Oncogene 17:3007–3013

    Article  PubMed  CAS  Google Scholar 

  • Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075

    Article  PubMed  CAS  Google Scholar 

  • Edelmann L, Edelmann W (2004) Loss of DNA mismatch repair function and cancer predisposition in the mouse: animal models for human hereditary nonpolyposis colorectal cancer. Am J Med Genet C Semin Med Genet 129C:91–99

    Article  PubMed  Google Scholar 

  • Ehrlich M, Zhang X-Y, Inamdar NM (1990) Spontaneous deamination of cytosine and 5-methylcytosine residues in DNA and replacement of 5-methylcytosine residues with cytosine residues. Mutation Res 238:277–286

    PubMed  CAS  Google Scholar 

  • Feldmeyer N, Schmeiser HH, Muehlbauer KR, Belharazem D, Knyazev Y, Nedelko T, Hollstein M (2006) Further studies with a cell immortalization assay to investigate the mutation signature of aristolochic acid in human p53 sequences. Mutat Res 608:163–168

    PubMed  CAS  Google Scholar 

  • Felley-Bosco E, Mirkovitch J, Ambs S, Mace K, Pfeifer A, Keefer LK, Harris CC (1995) Nitric oxide and ethylnitrosourea: relative mutagenicity in the p53 tumor suppressor and hypoxanthine-phosphoribosyltransferase genes. Carcinogenesis 16:2069–2074

    Article  PubMed  CAS  Google Scholar 

  • Feng Z, Hu W, Chen JX, Pao A, Li H, Rom W, Hung MC, Tang MS (2002) Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer. J Natl Cancer Inst 94:1527–1536

    PubMed  CAS  Google Scholar 

  • Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, Clements J, Menzies A, Teague JW, Futreal PA, Stratton MR (2008) The catalogue of somatic mutations in cancer (COSMIC). Curr Protoc Hum Genet Chapter 10: Unit 10.11

  • Frederico LA, Kunkel TA, Shaw BR (1990) A sensitive genetic assay for the detection of cytosine deamination: determination of rate constants and the activation energy. Biochemistry 29:2532–2537

    Article  PubMed  CAS  Google Scholar 

  • Fronza G, Inga A, Monti P, Scott G, Campomenosi P, Menichini P, Ottaggio L, Viaggi S, Burns PA, Gold B, Abbondandolo A (2000) The yeast p53 functional assay: a new tool for molecular epidemiology. Hopes and facts. Mutat Res 462:293–301

    Article  PubMed  CAS  Google Scholar 

  • Gee P, Maron DM, Ames BN (1994) Detection and classification of mutagens: a set of base-specific Salmonella tester strains. Proc Natl Acad Sci USA 91:11606–11610

    Article  PubMed  CAS  Google Scholar 

  • Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O’Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153–158

    Article  PubMed  CAS  Google Scholar 

  • Grollman AP, Shibutani S, Moriya M, Miller F, Wu L, Moll U, Suzuki N, Fernandes A, Rosenquist T, Medverec Z, Jakovina K, Brdar B, Slade N, Turesky RJ, Goodenough AK, Rieger R, Vukelic M, Jelakovic B (2007) Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci USA 104:12129–12134

    Article  PubMed  CAS  Google Scholar 

  • Hainaut P, Pfeifer GP (2001) Patterns of p53 G→T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. Carcinogenesis 22:367–374

    Article  PubMed  CAS  Google Scholar 

  • Hainaut P, Wiman KG (2005) 25 years of p53 research. Springer, Dordrecht

    Book  Google Scholar 

  • Hamroun D, Kato S, Ishioka C, Claustres M, Beroud C, Soussi T (2006) The UMD TP53 database and website: update and revisions. Hum Mutat 27:14–20

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  • Hanawalt PC (2002) Subpathways of nucleotide excision repair and their regulation. Oncogene 21:8949–8956

    Article  PubMed  CAS  Google Scholar 

  • Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91:1194–1210

    Article  PubMed  CAS  Google Scholar 

  • Hendrich B, Hardeland U, Ng H-H, Jiricny J, Bird A (1999) The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature 401:301–304

    Article  PubMed  CAS  Google Scholar 

  • Hofseth LJ, Hussain SP, Harris CC (2004) p53: 25 years after its discovery. Trends Pharmacol Sci 25:177–181

    Article  PubMed  CAS  Google Scholar 

  • Hollstein M, Marion MJ, Lehman T, Welsh J, Harris CC, Martel-Planche G, Kusters I, Montesano R (1994) p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. Carcinogenesis 15:1–3

    Article  PubMed  CAS  Google Scholar 

  • Husgafvel-Pursiainen K, Hackman P, Ridanpaa M, Anttila S, Karjalainen A, Partanen T, Taikina-Aho O, Heikkila L, Vainio H (1993) K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos. Int J Cancer 53:250–256

    Article  PubMed  CAS  Google Scholar 

  • Hussain SP, Harris CC (1998) Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res 58:4023–4037

    PubMed  CAS  Google Scholar 

  • Hussain SP, Hollstein MH, Harris CC (2000) p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology, and human risk assessment. Ann NY Acad Sci 919:79–85

    Article  PubMed  CAS  Google Scholar 

  • Hussain SP, Schwank J, Staib F, Wang XW, Harris CC (2007) TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene 26:2166–2176

    Article  PubMed  CAS  Google Scholar 

  • Jackson MA, Lea I, Rashid A, Peddada SD, Dunnick JK (2006) Genetic alterations in cancer knowledge system: analysis of gene mutations in mouse and human liver and lung tumors. Toxicol Sci 90:400–418

    Article  PubMed  CAS  Google Scholar 

  • Jaworski M, Hailfinger S, Buchmann A, Hergenhahn M, Hollstein M, Ittrich C, Schwarz M (2005) Human p53 knock-in (hupki) mice do not differ in liver tumor response from their counterparts with murine p53. Carcinogenesis 26:1829–1834

    Article  PubMed  CAS  Google Scholar 

  • Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  PubMed  CAS  Google Scholar 

  • Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806

    Article  PubMed  CAS  Google Scholar 

  • Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C (2003) Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA 100:8424–8429

    Article  PubMed  CAS  Google Scholar 

  • Kohara A, Suzuki T, Honma M, Ohwada T, Hayashi M (2002) Mutagenicity of aristolochic acid in the lambda/lacZ transgenic mouse (MutaMouse). Mutat Res 515:63–72

    PubMed  CAS  Google Scholar 

  • Krawczak M, Ball EV, Cooper DN (1998) Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am J Hum Genet 63:474–488

    Article  PubMed  CAS  Google Scholar 

  • Kusumoto R, Masutani C, Iwai S, Hanaoka F (2002) Translesion synthesis by human DNA polymerase eta across thymine glycol lesions. Biochemistry 41:6090–6099

    Article  PubMed  CAS  Google Scholar 

  • Lambert IB, Singer TM, Boucher SE, Douglas GR (2005) Detailed review of transgenic rodent mutation assays. Mutat Res 590:1–280

    PubMed  CAS  Google Scholar 

  • Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362:709–715

    Article  PubMed  CAS  Google Scholar 

  • Liu Z, Hergenhahn M, Schmeiser HH, Wogan GN, Hong A, Hollstein M (2004) Human tumor p53 mutations are selected for in mouse embryonic fibroblasts harboring a humanized p53 gene. Proc Natl Acad Sci USA 101:2963–2968

    Article  PubMed  CAS  Google Scholar 

  • Liu Z, Muehlbauer KR, Schmeiser HH, Hergenhahn M, Belharazem D, Hollstein MC (2005) p53 mutations in benzo(a)pyrene-exposed human p53 knock-in murine fibroblasts correlate with p53 mutations in human lung tumors. Cancer Res 65:2583–2587

    Article  PubMed  CAS  Google Scholar 

  • Loeb LA, Bielas JH, Beckman RA (2008) Cancers exhibit a mutator phenotype: clinical implications. Cancer Res 68:3551–3557 (discussion 3557)

    Article  PubMed  CAS  Google Scholar 

  • Lord GM, Cook T, Arlt VM, Schmeiser HH, Williams G, Pusey CD (2001) Urothelial malignant disease and Chinese herbal nephropathy. Lancet 358:1515–1516

    Article  PubMed  CAS  Google Scholar 

  • Lord GM, Hollstein M, Arlt VM, Roufosse C, Pusey CD, Cook T, Schmeiser HH (2004) DNA adducts and p53 mutations in a patient with aristolochic acid-associated nephropathy. Am J Kidney Dis 43:e11–e17

    Article  PubMed  Google Scholar 

  • Luch A (2005) Nature and nurture—lessons from chemical carcinogenesis. Nat Rev Cancer 5:113–125

    Article  PubMed  CAS  Google Scholar 

  • Luo JL, Tong WM, Yoon JH, Hergenhahn M, Koomagi R, Yang Q, Galendo D, Pfeifer GP, Wang ZQ, Hollstein M (2001a) UV-induced DNA damage and mutations in Hupki (human p53 knock-in) mice recapitulate p53 hotspot alterations in sun-exposed human skin. Cancer Res 61:8158–8163

    PubMed  CAS  Google Scholar 

  • Luo JL, Yang Q, Tong WM, Hergenhahn M, Wang ZQ, Hollstein M (2001b) Knock-in mice with a chimeric human/murine p53 gene develop normally and show wild-type p53 responses to DNA damaging agents: a new biomedical research tool. Oncogene 20:320–328

    Article  PubMed  CAS  Google Scholar 

  • Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932

    Article  PubMed  CAS  Google Scholar 

  • Marshall CJ, Vousden KH, Phillips DH (1984) Activation of c-Ha-ras-1 proto-oncogene by in vitro modification with a chemical carcinogen, benzo(a)pyrene diol-epoxide. Nature 310:586–589

    Article  PubMed  CAS  Google Scholar 

  • Millar CB, Guy J, Sansom OJ, Selfridge J, MacDougall E, Hendrich B, Keightley PD, Bishop SM, Clarke AR, Bird A (2002) Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297:403–405

    Article  PubMed  CAS  Google Scholar 

  • Montesano R, Hainaut P, Wild CP (1997) Hepatocellular carcinoma: from gene to public health. J Natl Cancer Inst 89:1844–1851

    Article  PubMed  CAS  Google Scholar 

  • Mossman BT, Klein G, Zur Hausen H (2004) Modern criteria to determine the etiology of human carcinogens. Semin Cancer Biol 14:449–452

    Article  PubMed  CAS  Google Scholar 

  • Neddermann P, Gallinari P, Lettieri T, Schmid D, Truong O, Hsuan JJ, Wiebauer K, Jiricny J (1996) Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase. J Biol Chem 271:12767–12774

    Article  PubMed  CAS  Google Scholar 

  • Nedelko T, Arlt VM, Phillips DH, Hollstein M (2009) TP53 mutation signature supports involvement of aristolochic acid in the aetiology of endemic nephropathy-associated tumours. Int J Cancer 124:987–990

    Article  PubMed  CAS  Google Scholar 

  • Nortier JL, Martinez MC, Schmeiser HH, Arlt VM, Bieler CA, Petein M, Depierreux MF, De Pauw L, Abramowicz D, Vereerstraeten P, Vanherweghem JL (2000) Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 342:1686–1692

    Article  PubMed  CAS  Google Scholar 

  • Olivier M, Hussain SP, Caron de Fromentel C, Hainaut P, Harris CC (2004) TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ: 247-270

  • Parada LF, Tabin CJ, Shih C, Weinberg RA (1982) Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297:474–478

    Article  PubMed  CAS  Google Scholar 

  • Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  PubMed  CAS  Google Scholar 

  • Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M (2007) TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26:2157–2165

    Article  PubMed  CAS  Google Scholar 

  • Pfau W, Schmeiser HH, Wiessler M (1990) Aristolochic acid binds covalently to the exocyclic amino group of purine nucleotides in DNA. Carcinogenesis 11:313–319

    Article  PubMed  CAS  Google Scholar 

  • Pfeifer GP (2000) p53 mutational spectra and the role of methylated CpG sequences. Mutat Res 450:155–166

    PubMed  CAS  Google Scholar 

  • Pfeifer GP (2006) Mutagenesis at methylated CpG sequences. Curr Top Microbiol Immunol 301:259–281

    Article  PubMed  CAS  Google Scholar 

  • Pfeifer GP, Drouin R, Riggs AD, Holmquist GP (1991) In vivo mapping of a DNA adduct at nucleotide resolution: detection of pyrimidine (6–4) pyrimidone photoproducts by ligation-mediated polymerase chain reaction. Proc Natl Acad Sci USA 88:1374–1378

    Article  PubMed  CAS  Google Scholar 

  • Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P (2002) Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21:7435–7451

    Article  PubMed  CAS  Google Scholar 

  • Pfeifer GP, You YH, Besaratinia A (2005) Mutations induced by ultraviolet light. Mutat Res 571:19–31

    PubMed  CAS  Google Scholar 

  • Quintanilla M, Brown K, Ramsden M, Balmain A (1986) Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322:78–80

    Article  PubMed  CAS  Google Scholar 

  • Rajagopalan H, Lengauer C (2004) Aneuploidy and cancer. Nature 432:338–341

    Article  PubMed  CAS  Google Scholar 

  • Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, Wang Z, Riggs AD, Pfeifer GP (2008) High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proc Natl Acad Sci USA 105:252–257

    Article  PubMed  CAS  Google Scholar 

  • Reinbold M, Luo JL, Nedelko T, Jerchow B, Murphy ME, Whibley C, Wei Q, Hollstein M (2008) Common tumour p53 mutations in immortalized cells from Hupki mice heterozygous at codon 72. Oncogene 27:2788–2794

    Article  PubMed  CAS  Google Scholar 

  • Rideout WMIII, Coetzee GA, Olumi AF, Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249:1288–1290

    Article  PubMed  CAS  Google Scholar 

  • Ruggeri B, DiRado M, Zhang SY, Bauer B, Goodrow T, Klein-Szanto AJP (1993) Benzo[a]pyrene-induced murine skin tumors exhibit frequent and characteristic G to T mutations in the p53 gene. Proc Natl Acad Sci USA 90:1013–1017

    Article  PubMed  CAS  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554

    Article  PubMed  CAS  Google Scholar 

  • Schmutte C, Jones PA (1998) Involvement of DNA methylation in human carcinogenesis. Biol Chem 379:377–388

    Article  PubMed  CAS  Google Scholar 

  • Schmutte C, Yang AS, Beart RW, Jones PA (1995) Base excision repair of U:G mismatches at a mutational hotspot in the p53 gene is more efficient than base excision repair of T:G mismatches in extracts of human colon tumors. Cancer Res 55:3742–3746

    PubMed  CAS  Google Scholar 

  • Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181

    Article  PubMed  CAS  Google Scholar 

  • Shen JC, Rideout WMIII, Jones PA (1994) The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. Nucleic Acids Res 22:972–976

    Article  PubMed  CAS  Google Scholar 

  • Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274

    Article  PubMed  CAS  Google Scholar 

  • Smith LE, Denissenko MF, Bennett WP, Li H, Amin S, Tang M-S, Pfeifer GP (2000) Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons. J Natl Cancer Inst 92:803–811

    Article  PubMed  CAS  Google Scholar 

  • Soussi T, Beroud C (2003) Significance of TP53 mutations in human cancer: a critical analysis of mutations at CpG dinucleotides. Hum Mutat 21:192–200

    Article  PubMed  CAS  Google Scholar 

  • Sukumar S, Notario V, Martin-Zanca D, Barbacid M (1983) Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature 306:658–661

    Article  PubMed  CAS  Google Scholar 

  • Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M, Wigler M (1982) Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300:762–765

    Article  PubMed  CAS  Google Scholar 

  • Thilly WG (1990) Mutational spectrometry in animal toxicity testing. Annu Rev Pharmacol Toxicol 30:369–385

    Article  PubMed  CAS  Google Scholar 

  • Thilly WG (2003) Have environmental mutagens caused oncomutations in people? Nat Genet 34:255–259

    Article  PubMed  CAS  Google Scholar 

  • Tommasi S, Denissenko MF, Pfeifer GP (1997) Sunlight induces pyrimidine dimers preferentially at 5-methylcytosine bases. Cancer Res 57:4727–4730

    PubMed  CAS  Google Scholar 

  • Tong WM, Lee MK, Galendo D, Wang ZQ, Sabapathy K (2006) Aflatoxin-B exposure does not lead to p53 mutations but results in enhanced liver cancer of Hupki (human p53 knock-in) mice. Int J Cancer 119:745–749

    Article  PubMed  CAS  Google Scholar 

  • Tornaletti S, Pfeifer GP (1995) Complete and tissue-independent methylation of CpG sites in the p53 gene: implications for mutations in human cancers. Oncogene 10:1493–1499

    PubMed  CAS  Google Scholar 

  • Toyooka S, Tsuda T, Gazdar AF (2003) The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat 21:229–239

    Article  PubMed  CAS  Google Scholar 

  • US-EPA (Gilman P (2002) Health Assessment Document for Diesel Engine Exhaust. In: U.S. Environmental Protection Agency NCfEA (ed) Washington, DC

  • Vineis P, Perera F (2007) Molecular epidemiology and biomarkers in etiologic cancer research: the new in light of the old. Cancer Epidemiol Biomarkers Prev 16:1954–1965

    Article  PubMed  CAS  Google Scholar 

  • Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310

    Article  PubMed  CAS  Google Scholar 

  • vom Brocke J, Schmeiser HH, Reinbold M, Hollstein M (2006) MEF immortalization to investigate the ins and outs of mutagenesis. Carcinogenesis 27:2141–2147

    Article  PubMed  CAS  Google Scholar 

  • vom Brocke J, Krais A, Whibley C, Hollstein MC, Schmeiser HH (2008) The carcinogenic air pollutant 3-nitrobenzanthrone induces GC to TA transversion mutations in human p53 sequences. Mutagenesis 24:17–23

    Article  PubMed  CAS  Google Scholar 

  • Walker DR, Bond JP, Tarone RE, Harris CC, Makalowski W, Boguski MS, Greenblatt MS (1999) Evolutionary conservation and somatic mutation hotspot maps of p53: correlation with p53 protein structural and functional features. Oncogene 18:211–218

    Article  PubMed  CAS  Google Scholar 

  • Wang TL, Rago C, Silliman N, Ptak J, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE (2002) Prevalence of somatic alterations in the colorectal cancer cell genome. Proc Natl Acad Sci USA 99:3076–3080

    Article  PubMed  CAS  Google Scholar 

  • Wink DA, Kasprzak KS, Maragos CM, Elespuru RK, Misra M, Dunams TM, Cebula TA, Koch WH, Andrews AW, Allen JS, Keefe LK (1991) DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 254:1001–1003

    Article  PubMed  CAS  Google Scholar 

  • Wong E, Yang K, Kuraguchi M, Werling U, Avdievich E, Fan K, Fazzari M, Jin B, Brown AM, Lipkin M, Edelmann W (2002) Mbd4 inactivation increases C to T transition mutations and promotes gastrointestinal tumor formation. Proc Natl Acad Sci USA 99:14937–14942

    Article  PubMed  CAS  Google Scholar 

  • Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113

    Article  PubMed  CAS  Google Scholar 

  • Yoon JH, Smith LE, Feng Z, Tang M, Lee CS, Pfeifer GP (2001) Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res 61:7110–7117

    PubMed  CAS  Google Scholar 

  • You YH, Li C, Pfeifer GP (1999) Involvement of 5-methylcytosine in sunlight-induced mutagenesis. J Mol Biol 293:493–503

    Article  PubMed  CAS  Google Scholar 

  • Zarbl H, Sukumar S, Arthur AV, Martin-Zanca D, Barbacid M (1985) Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. Nature 315:382–385

    Article  PubMed  CAS  Google Scholar 

  • Zuo S, Boorstein RJ, Teebor GW (1995) Oxidative damage to 5-methylcytosine in DNA. Nucleic Acids Res 25:3239–3243

    Article  Google Scholar 

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Acknowledgments

Work of the authors is supported by NIH grant CA084469 to G.P.P.

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  1. Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA

    Gerd P. Pfeifer & Ahmad Besaratinia

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  1. Gerd P. Pfeifer
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  2. Ahmad Besaratinia
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Correspondence to Gerd P. Pfeifer.

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Pfeifer, G.P., Besaratinia, A. Mutational spectra of human cancer. Hum Genet 125, 493–506 (2009). https://doi.org/10.1007/s00439-009-0657-2

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