Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers

Oncogene volume 21, pages 7435–7451 (2002)Cite this article

Abstract

It is estimated that cigarette smoking kills over 1 000 000 people each year by causing lung cancer as well as many other neoplasmas. p53 mutations are frequent in tobacco-related cancers and the mutation load is often higher in cancers from smokers than from nonsmokers. In lung cancers, the p53 mutational patterns are different between smokers and nonsmokers with an excess of G to T transversions in smoking-associated cancers. The prevalence of G to T transversions is 30% in smokers’ lung cancer but only 12% in lung cancers of nonsmokers. A similar trend exists, albeit less marked, in laryngeal cancers and in head and neck cancers. This type of mutation is infrequent in most other tumors aside from hepatocellular carcinoma. At several p53 mutational hotspots common to all cancers, such as codons 248 and 273, a large fraction of the mutations are G to T events in lung cancers but are almost exclusively G to A transitions in non-tobacco-related cancers. Two important classes of tobacco smoke carcinogens are the polycyclic aromatic hydrocarbons (PAH) and the nicotine-derived nitrosamines. Recent studies have indicated that there is a strong coincidence of G to T transversion hotspots in lung cancers and sites of preferential formation of PAH adducts along the p53 gene. Endogenously methylated CpG dinucleotides are the preferred sites for G to T transversions, accounting for more than 50% of such mutations in lung tumors. The same dinucleotide, when present within CpG-methylated mutational reporter genes, is the target of G to T transversion hotspots in cells exposed to the model PAH compound benzo[a]pyrene-7,8-diol-9,10-epoxide. As summarized here, a number of other tobacco smoke carcinogens also can cause G to T transversion mutations. The available data suggest that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Armstrong RN . 1997 Comprehensive Toxicology: Biotransformation. Vol 3. Guengerich FP (ed) New York: Elsevier Science pp. 307–327

    Google Scholar 

  • Arora A, Willhite C, Liebler D . 2001 Carcinogenesis 22: 1173–1178

  • Asami S, Manabe H, Miyake J, Tsurudome Y, Hirano T, Yamaguchi R, Itoh H, Kasai H . 1997 Carcinogenesis 18: 1763–1766

  • Bennett WP, Hussain SP, Vahakangas KH, Khan MA, Sheilds PG, Harris CC . 1999 J. Pathol. 187: 8–18

  • Besarati Nia A, Kleinjans JC, Van Schooten FJ . 2002a Biomarkers 7: 209–229

  • Besarati Nia A, Bates SE, Pfeifer GP . 2002b Cancer Res. 62: (in press)

  • Bigger C, St John J, Yagi H, Jerina D, Dipple A . 1992 Proc. Natl. Acad. Sci. USA 89: 368–372

  • Brennan JA, Boyle JO, Koch WM, Goodman SN, Hruban RH, Eby YJ, Couch MJ, Forastiere AA, Sidransky D . 1995 New Engl. J. Med. 332: 712–717

  • Burchell B, McGurk K, Brierley C, Clarke D . 1997 Comprehensive Toxicology: Biotransformation. Vol 3. Guengerich FP (ed) New York: Elsevier Science pp. 401–436

    Google Scholar 

  • Burney S, Caulfield J, Niles J, Wishnok J, Tannenbaum S . 1999 Mutation Res. 424: 37–49

  • Carmical J, Zhang M, Nechev L, Harris C, Harris T, Lloyd R . 2000 Chem. Res. Toxicol. 13: 18–25

  • Casale G, Singhal M, Bhattacharya S, Ramanathan R, Roberts K, Barbacci D, Zhao J, Jankowiak R, Gross M, Cavalieri E, Small G, Rennard S, Mumford J, Shen M . 2001 Chem. Res. Toxicol. 14: 192–201

  • Castelao J, Yuan J, Skipper P, Tannenbaum S, Gago-Dominguez M, Crowder J, Ross R, Yu M . 2001 J. Natl. Cancer Inst. 93: 538–545

  • Chao A, Thun M, Jacobs E, Henley S, Rodriguez C, Calle E . 2000 J. Natl. Cancer Inst. 92: 1888–1896

  • Chen JX, Zheng Y, West M, Tang M-S . 1998 Cancer Res. 58: 2070–2075

  • Chen R-H, Maher VM, McCormick JJ . 1990 Proc. Natl. Acad. Sci. USA 87: 8680–8684

  • Chepiga T, Morton M, Murphy P, Avalos J, Bombick B, Doolittle D, Borgerding M, Swauger J . 2000 Food Chem. Toxicol. 38: 949–962

  • Chung F, Zhang L, Ocando J, Nath R . 1999 Exocyclic DNA Adducts in Mutagenesis and Carcinogenesis. Singer B and Bartsch H (eds) Lyon, France: International Agency for Research on Cancer pp. 45–54

    Google Scholar 

  • Conney A . 1982 Cancer Res. 42: 4875–4917

  • Culp S, Gaylor D, Sheldon W, Goldstein L, Beland F . 1998 Carcinogenesis 19: 117–124

  • Culp S, Roberts D, Talaska G, Lang N, Fu P, Lay Jr J, Teitel C, Snawder J, Von Tungeln L, Kadlubar F . 1997 Mutation Res. 378: 97–112

  • Das A, Tan KS, Gopalakrishnan S, Waring MJ, Tomasz M . 1999 Chem. Biol. 6: 461–471

  • Delclos K, Kadlubar F . 1997 Comprehensive Toxicology: Chemical Carcinogens and Anticarcinogens. 12th edn. Bowden GT and Fischer SM (eds). pp. 141–170

  • DeMarini DM, Landi S, Tian D, Hanley NM, Li X, Hu F, Roop BC, Mass MJ, Keohavong P, Gao W, Olivier M, Hainaut P, Mumford JL . 2001 Cancer Res. 61: 6679–6681

  • Denissenko MF, Chen JX, Tang MS, Pfeifer GP . 1997 Proc. Natl. Acad. Sci. USA 94: 3893–3898

  • Denissenko MF, Pao A, Pfeifer GP, Tang M-S . 1998 Oncogene 16: 1241–1247

  • Denissenko MF, Pao A, Tang M-S, Pfeifer GP . 1996 Science 274: 430–432

  • Deutsch-Wenzel R, Brune H, Grimmer G, Dettbarn G, Misfield J . 1983 J. Natl. Cancer Inst. 71: 539–543

  • Doll R . 1996 Br. Med. J. 52: 35–49

  • Duffel M . 1997 Comprehensive Toxicology: Biotransformation. Vol 3. Guengerich FP (ed) New York: Elsevier Science pp. 365–384

    Google Scholar 

  • Eisenstadt E, Warren AJ, Porter J, Atkins D, Miller JH . 1982 Proc. Natl. Acad. Sci. USA 79: 1945–1949

  • Feng Z, Hu W, Rom WN, Beland FA, Tang M-S . 2002 Biochemistry 41: 6414–6421

  • Foiles PG, Akerkar SA, Carmella SG, Kagan M, Stoner GD, Resau JH, Hecht SS . 1991 Chem. Res. Toxicol. 4: 364–368

  • Geacintov NE . 1986 Carcinogenesis 7: 759–766

  • Greenblatt MS, Bennett WP, Hollstein M, Harris CC . 1994 Cancer Res. 54: 4855–4878

  • Guengerich F . 2001 Chem. Res. Toxicol. 14: 611–650

  • Guengerich F, Kim D . 1991 Chem. Res. Toxicol. 4: 413–421

  • Gupta R, Arif J, Gairola C . 1999 Mutation Res. 424: 195–205

  • Hainaut P, Hollstein M . 2000 Adv. Cancer Res. 77: 81–137

  • Hainaut P, Olivier M, Pfeifer GP . 2001 Mutagenesis 16: 551–553

  • Hainaut P, Pfeifer GP . 2001 Carcinogenesis 22: 367–374

  • Hanahan D, Weinberg R . 2000 Cell 100: 57–70

  • Harley N, Cohen B, Tso T . 1980 Banbury Report 3: A Safe Cigarette? Gori GB and Beck FG (eds) Cold Spring Harbor Laboratory pp. 93–104

    Google Scholar 

  • Hecht S, Hoffmann D . 1988 Carcinogenesis 9: 875–884

  • Hecht S, Rivenson A, Braley J, DiBello J, Adams J, Hoffmann D . 1986 Cancer Res. 46: 4162–4166

  • Hecht S, Tricker A . 1999 III. Analytical Determination of Nicotine and Related Compounds and Their Metabolites. Gorrod JW and Jacob P (eds) Amsterdam: Elsevier Science pp. 421–488

    Book  Google Scholar 

  • Hecht SS . 1998 Chem. Res. Toxicol. 11: 559–603

  • Hecht SS . 1999 J. Natl. Cancer Inst. 91: 1194–1210

  • Henderson P, Delaney J, Gu F, Tannenbaum S, Essigmann J . 2002 Biochemistry 41: 914–921

  • Hernandez-Boussard TM, Hainaut P . 1998 Environ. Health Perspect. 106: 385–391

  • Hoeijmakers JH . 2001 Nature 411: 366–374

  • Hoffmann D, Hecht S . 1990 Handbook of Experimental Pharmacology. 94/1 ed. Cooper CS and Grover PL (eds) Heidelberg: Springer-Verlag pp. 63–102

    Google Scholar 

  • Hoffmann D, Hoffmann I, El-Bayoumy K . 2001 Chem. Res. Toxicol. 14: 767–790

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC . 1991 Science 253: 49–53

  • Husgafvel-Pursiainen K, Kannio A . 1996 Environ. Health Perspect. 104: Suppl. 3 553–556

  • Hussain SP, Amstad P, Raja K, Sawyer M, Hofseth L, Shields PG, Hewer A, Phillips DH, Ryberg D, Haugen A, Harris CC . 2001 Cancer Res. 61: 6350–6355

  • Hussain SP, Harris CC . 1998 Cancer Res. 58: 4023–4037

  • International Agency for Research on Cancer. 1972 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Vol 1 Lyon, France: IARC

  • International Agency for Research on Cancer. 1973 IARC Monographs on the Carcinogenic Risk of Chemicals to Man. Vol 4 Lyon, France: IARC pp. 127–136

  • International Agency for Research on Cancer. 1974a IARC Monographs on the Carcinogenic Risk of Chemicals to Man. Vol 7 Lyon, France: IARC pp. 111–140

  • International Agency for Research on Cancer. 1974b IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 4 Lyon, France: IARC pp. 97–111

  • International Agency for Research on Cancer. 1978 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Vol 17 Lyon, France: IARC pp. 83–124

  • International Agency for Research on Cancer. 1982 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 29 Lyon, France: IARC pp. 93–148

  • International Agency for Research on Cancer. 1983 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 32 Lyon, France: IARC pp. 211–224

  • International Agency for Research on Cancer. 1985 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 36 Lyon, France: IARC pp. 101–132

  • International Agency for Research on Cancer. 1986a IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 60 Lyon, France: IARC pp. 73–159

  • International Agency for Research on Cancer. 1986b IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 38 Lyon, France: IARC pp. 37–375

  • International Agency for Research on Cancer. 1992 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 54 Lyon, France: IARC pp. 237–285

  • International Agency for Research on Cancer. 1999 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol 71 Lyon, France: IARC pp. 109–225

  • Johnson RE, Prakash S, Prakash L . 1999 Science 283: 1001–1004

  • Koc H, Tretyakova N, Walker V, Henderson R, Swenberg J . 1999 Chem. Rev. Toxicol. 12: 566–574

  • Koivisto P, Kilpelainen I, Rasanen I, Adler I, Pacchierotti F, Peltonen K . 1999 Carcinogenesis 20: 1253–1259

  • Kozack R, Seo K, Jelinsky S, Loechler E . 2000 Mutation Res. 450: 41–59

  • Kriek E, Rojas M, Alexandrov K, Bartsch H . 1998 Mutation Res. 400: 215–231

  • Kunkel T . 1984 Proc. Natl. Acad. Sci. USA 81: 1494–1498

  • Lin D, Lay JO, Bryant MS, Malaveille C, Friesen M, Bartsch H, Lang NP, Kadlubar FF . 1994 Environ. Health Perspect. 102: Suppl. 6 11–16

  • Livneh Z . 2001 J. Biol. Chem. 276: 25639–25642

  • Loechler E, Green C, Essigmann J . 1984 Proc. Natl. Acad. Sci. USA 81: 6271–6275

  • Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, Araki M, Iwai S, Takio K, Hanaoka F . 1999 Nature 399: 700–704

  • Mazur M, Glickman B . 1988 Somat. Cell Mol. Genet. 14: 393–400

  • McCoy G, Wynder E . 1979 Cancer Res. 39: 2844–2850

  • Melchior Jr W, Marques M, Beland F . 1994 Carcinogenesis 15: 889–899

  • Melikian A, Amin S, Huie K, Hecht S, Harvey R . 1988 Cancer Res. 48: 1781–1787

  • Melikian A, Fudem Goldin B, Prahalad A, Hecht S . 1990 Chem. Res. Toxicol. 3: 139–143

  • Miller J . 1994 Drug Metabol. Dispos. 26: 1–36

  • Misra R, Page J, Smith G, Waalkes M, Dipple A . 1998 Chem. Res. Toxicol. 11: 211–216

  • Moriya M . 1993 Proc. Natl. Acad. Sci. USA 90: 1122–1126

  • Nair J, Barbin A, Velic I, Bartsch H . 1999 Mutation Res. 424: 59–69

  • National Toxicology Program. 1986 NTP Technical Report No. 289, Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies) National Toxicology Program

  • Nesnow S, Ross J, Stoner G, Mass M . 1995 Toxicology 103: 403–413

  • Noori P, Hou S . 2001 Carcinogenesis 22: 1825–1830

  • Ory K, Legros Y, Auguin C, Soussi T . 1994 EMBO J. 13: 3496–3504

  • Paschke T . 2000 Mutagenesis 15: 457–458

  • Pauly GT, Peterson LA, Moschel RC . 2002 Chem. Res. Toxicol. 15: 165–169

  • Penning T, Burczynski M, Hung C, McCoull K, Palackal N, Tsuruda L . 1999 Chem. Res. Toxicol. 12: 1–18

  • Pfeifer GP . 2000 Mutat. Res. 450: 155–166

  • Pfeifer GP, Denissenko MF . 1998 Environ. Mol. Mutagen. 31: 197–205

  • Phillips DH . 1983 Nature 303: 468–472

  • Preussmann R, Stewart B . 1984 Chemical Carcinogens. 2nd ed. Vol 2. ACS Monograph 182. Searle CE (ed) Washington, DC: American Chemical Society pp. 643–828

    Google Scholar 

  • Proctor RN . 2001 Nature Reviews Cancer 1: 82–86

  • Pryor W . 1997 Environ. Health Perspect. 105: 875–882

  • Recio L, Saranko C, Steen A . 2000 Res. Rep. Health Eff. Inst. 49–87

  • Reznik-Shuller H . 1983 Comparative Respiratory Tract Carcinogens 2nd edn Reznik-Shuller HM (ed) Boca Raton, FL: CRC Press pp. 109–159

    Google Scholar 

  • Rivenson A, Hoffmann D, Prokopczyk B, Amin S, Hecht S . 1988 Cancer Res. 48: 6912–6917

  • Rodin SN, Rodin AS . 2000 Proc. Natl. Acad. Sci. USA 97: 12244–12249

  • Rojas M, Alexandrov K, Cascarbi I, Brockmoller J, Likhachev A, Pozharisski K, Bouvier G, Auburtin G, Mayer L, Koop-Schneider A, Roots I, Bartsch H . 1998 Pharmacogenetics 8: 109–118

  • Ronai ZA, Gradia S, Peterson LA, Hecht SS . 1993 Carcinogenesis 14: 2419–2422

  • Ross J, Nesnow S . 1999 Mutation Res. 424: 155–166

  • Rubin H . 2001 Carcinogenesis 22: 1903–1930

  • Ruggeri B, DiRado M, Zhang SY, Bauer B, Goodrow T, Klein-Szanto AJP . 1993 Proc. Natl. Acad. Sci. USA 90: 1013–1017

  • Santella R . 1999 Cancer Epidemiol. Biomarkers Prev. 8: 733–739

  • Schüller H, Jorquera R, Reichert A, Castonguay A . 1993 Cancer Res. 53: 2498–2501

  • Sellakumar A, Shubik P . 1974 J. Natl. Cancer Inst. 53: 1713–1719

  • Seo K, Jelinsky S, Loechler E . 2000 Mutation Res. 463: 215–246

  • Singer B, Grunberger D . 1983 Molecular Biology of Mutagens and Carcinogens New York: Plenum Press pp. 45–94

  • Smith LE, Denissenko MF, Bennett WP, Li H, Amin S, Tang M-S, Pfeifer GP . 2000 J. Natl. Cancer Inst. 92: 803–811

  • Snook M, Severson R, Arrendale R, Higman H, Chortyk O . 1978 Beiträge Tabakforsch. 9: 222–247

  • Sodum R, Fiala E . 1998 Chem. Res. Toxicol. 11: 1453–1459

  • Solt D, Polverini P, Claderon L . 1987 J. Oral Path. 16: 294–302

  • Spiegelhalder B, Bartsch H . 1996 Eur. J. Cancer Prev. 5: 33–38

  • Swenberg J, Bogdanffy M, Ham A, Holt S, Kim A, Morinello E, Ranasinghe A, Scheller N, Upton P . 1999 IARC Sci. Publ. 29–43

  • Swenberg J, Kerns W, Mitchell R, Gralla J, Pavkov K . 1980 Cancer Res. 40: 3398–3402

  • Szeliga J, Dipple A . 1998 Chem. Res. Toxicol. 11: 1–11

  • Tang D, Phillips D, Stampfer M, Mooney L, Hsu Y, Cho S, Tsai W, Ma J, Cole K, She M, Perera F . 2001 Cancer Res. 61: 6708–6712

  • Thornton-Manning JR, Dahl AR, Bechtold WE, Griffith Jr WC, Henderson RF . 1995 Carcinogenesis 16: 1723–1731

  • Tornaletti S, Pfeifer GP . 1995 Oncogene 10: 1493–1499

  • Tretyakova N, Lin Y, Sangaiah R, Upton P, Swenberg J . 1997 Carcinogenesis 18: 137–147

  • Vähäkangas KH, Bennett WP, Castrén K, Welsh JA, Khan MA, Blömeke B, Alavanja MC, Harris CC . 2001 Cancer Res 61: 4350–4356

  • Vineis P, Marinelli D, Autrup H, Brockmoller J, Cascorbi I, Daly A, Golka K, Okkels H, Risch A, Rothman N, Sim E, Taioli E . 2001 Cancer Epidemiol. Biomarkers Prev. 10: 1249–1252

  • Walker DR, Bond JP, Tarone RE, Harris CC, Makalowski W, Boguski MS, Greenblatt MS . 1999 Oncogene 18: 211–218

  • Wang M, McIntee E, Cheng G, Shi X, Villalta P, Hecht S . 2000a Chem. Res. Toxicol. 13: 1149–1157

  • Wang M, McIntee E, Cheng G, Shi Y, Villalta P, Hecht S . 2000b Chem. Res. Toxicol. 13: 1065–1074

  • Wang M, McIntee E, Cheng G, Shi Y, Villalta P, Hecht S . 2001a Chem. Res. Toxicol. 14: 423–430

  • Wang M, McIntee E, Shi Y, Cheng G, Upadhyaya P, Villalta P, Hecht S . 2001b Chem. Res. Toxicol. 14: 1435–1445

  • Wei SJ, Chang RL, Bhachech N, Cui XX, Merkler KA, Wong CQ, Hennig E, Yagi H, Jerina DM, Conney AH . 1993 Cancer Res. 53: 3294–3301

  • Weisenberger DJ, Romano LJ . 1999 J. Biol. Chem. 274: 23948–23955

  • Wilson VL, Weston A, Manchester DK, Trivers GE, Roberts DW, Kadlubar FF, Wild CP, Montesano R, Willey JC, Mann DL . 1989 Carcinogenesis 10: 2149–2153

  • Witschi H . 2000 Exp. Lung Res. 26: 743–755

  • World Health Organization. 1997 Tobacco or Health: A Global Status Report Geneva: WHO pp. 10–48

  • Yoon JH, Smith LE, Feng Z, Tang M, Lee CS, Pfeifer GP . 2001 Cancer Res. 61: 7110–7117

  • Zhang Y, Yuan F, Wu X, Rechkoblit O, Taylor JS, Geacintov NE, Wang Z . 2000 Nucleic Acids Res. 28: 4717–4724

  • Zhao C, Tyndyk M, Eide I, Hemminki K . 1999 Mutation Res. 424: 117–125

  • Zhao C, Vodicka P, Sram R, Hemminki K . 2000 Carcinogenesis 21: 107–111

Download references

Acknowledgements

The work of the authors was supported by grants from the National Institutes of Health (CA84469 to GP Pfeifer; CA-81301 and DA 13333 to SS Hecht). The IARC p53 database is supported by a grant from the European Community (QLG-1999-00273).

Author information

Authors and Affiliations

  1. Division of Biology, Beckman Research Institute of the City of Hope, Duarte, 91010, California, CA, USA

    Gerd P Pfeifer

  2. Sequenom Inc., San Diego, 92121, California, CA, USA

    Mikhail F Denissenko

  3. International Agency for Research on Cancer (WHO), 150 Cours Albert Thomas, Lyon cedex, 69372, France

    Magali Olivier & Pierre Hainaut

  4. University of Minnesota Cancer Center, Mayo Mail Code 806, 420 Delaware St. S.E., Minneapolis, 55455, Minnesota, MN, USA

    Natalia Tretyakova & Stephen S Hecht

Authors
  1. Gerd P Pfeifer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mikhail F Denissenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Magali Olivier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalia Tretyakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen S Hecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pierre Hainaut
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gerd P Pfeifer, Stephen S Hecht or Pierre Hainaut.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pfeifer, G., Denissenko, M., Olivier, M. et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21, 7435–7451 (2002). https://doi.org/10.1038/sj.onc.1205803

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205803

Keywords

This article is cited by

Search

Advanced search

Quick links