Skip to main content
SpringerLink
Log in

DNA Methylation Analysis Reveals a Strong Connection Between Tobacco Smoking and Cancer Pathogenesis

  • Chapter
  • First Online:
Tobacco Smoking Addiction: Epidemiology, Genetics, Mechanisms, and Treatment

  • 1461 Accesses

Abstract

Tobacco smoking is a well-documented risk factor for various cancers, especially those of the lung. To test our hypothesis that abnormal DNA methylation loci associated with smoking are enriched in genes and pathways implicated in the pathogenesis of cancer, we analyzed two sets of smoking-related methylated genes, in blood and buccal samples, as reported in 28 studies. By analyzing 320 methylated genes from 26 studies of blood samples, we found 57 enriched pathways associated with different types of cancer (false discovery rate [FDR] <0.05). Of these, 11 were also significantly overrepresented in the 661 methylated genes found in the 2 studies of buccal samples. We further found that the aryl hydrocarbon receptor signaling pathway plays an important role in the initiation of smoking-attributable cancer. Finally, we constructed a subnetwork of genes important for smoking-attributable cancer from the 48 nonredundant genes in the 11 oncogenic pathways. Of these, genes such as DUSP4 and AKT3 are well documented as being involved in smoking-related lung cancer. Taken together, these findings provide robust and systematic evidence in support of smoking’s impact on the epigenome, which may be an important contributor to cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Altucci L, Leibowitz MD, Ogilvie KM, de Lera AR, Gronemeyer H (2007) RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov 6:793–810. https://doi.org/10.1038/nrd2397

    Article  CAS  PubMed  Google Scholar 

  • Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40:616–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Armes JE, Hammet F, de Silva M, Ciciulla J, Ramus SJ, Soo W-K, Mahoney A, Yarovaya N, Henderson MA, Gish K (2004) Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers. Oncogene 23:5697–5702

    Article  CAS  PubMed  Google Scholar 

  • Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol 12:R10. https://doi.org/10.1186/gb-2011-12-1-r10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Britson J, Barton F, Balko JM, Black EP (2009) Deregulation of DUSP activity in EGFR-mutant lung cancer cell lines contributes to sustained ERK1/2 signaling. Biochem Biophs Res Co 390:849–854

    Article  CAS  Google Scholar 

  • CDC (2010) Racial/ethnic disparities and geographic differences in lung cancer incidence – 38 states and the District of Columbia, 1998–2006. MMWR Morb Mortal Wkly Rep 59:1434–1438

    Google Scholar 

  • Chitale D, Gong Y, Taylor BS, Broderick S, Brennan C, Somwar R, Golas B, Wang L, Motoi N, Szoke J (2009) An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 28:2773–2783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dogan MV, Shields B, Cutrona C, Gao L, Gibbons FX, Simons R, Monick M, Brody GH, Tan K, Beach SR, Philibert RA (2014) The effect of smoking on DNA methylation of peripheral blood mononuclear cells from African American women. BMC Genomics 15:151. https://doi.org/10.1186/1471-2164-15-151

    Article  PubMed  PubMed Central  Google Scholar 

  • Fasanelli F, Baglietto L, Ponzi E, Guida F, Campanella G, Johansson M, Grankvist K, Johansson M, Assumma MB, Naccarati A, Chadeau-Hyam M, Ala U, Faltus C, Kaaks R, Risch A, De Stavola B, Hodge A, Giles GG, Southey MC, Relton CL, Haycock PC, Lund E, Polidoro S, Sandanger TM, Severi G, Vineis P (2015) Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts. Nat Commun 6:10192. https://doi.org/10.1038/ncomms10192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiuza UM, Arias AM (2007) Cell and molecular biology of notch. J Endocrinol 194:459–474. https://doi.org/10.1677/JOE-07-0242

    Article  CAS  PubMed  Google Scholar 

  • Flom JD, Ferris JS, Liao Y, Tehranifar P, Richards CB, Cho YH, Gonzalez K, Santella RM, Terry MB (2011) Prenatal smoke exposure and genomic DNA methylation in a multiethnic birth cohort. Cancer Epidemiol Biomark Prev 20:2518–2523. https://doi.org/10.1158/1055-9965.EPI-11-0553

    Article  CAS  Google Scholar 

  • Furniss CS, Marsit CJ, Houseman EA, Eddy K, Kelsey KT (2008) Line region hypomethylation is associated with lifestyle and differs by human papillomavirus status in head and neck squamous cell carcinomas. Cancer Epidemiol Biomark Prev 17:966–971. https://doi.org/10.1158/1055-9965.EPI-07-2775

    Article  CAS  Google Scholar 

  • Gao X, Jia M, Zhang Y, Breitling LP, Brenner H (2015) DNA methylation changes of whole blood cells in response to active smoking exposure in adults: a systematic review of DNA methylation studies. Clin Epigenetics 7:113. https://doi.org/10.1186/s13148-015-0148-3

    Article  PubMed  PubMed Central  Google Scholar 

  • Grando SA (2014) Connections of nicotine to cancer. Nat Rev Cancer 14:419–429. https://doi.org/10.1038/nrc3725

    Article  CAS  PubMed  Google Scholar 

  • Gröschl B, Bettstetter M, Giedl C, Woenckhaus M, Edmonston T, Hofstädter F, Dietmaier W (2013) Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation. Int J Cancer 132:1537–1546

    Article  PubMed  Google Scholar 

  • Guida F, Sandanger TM, Castagne R, Campanella G, Polidoro S, Palli D, Krogh V, Tumino R, Sacerdote C, Panico S, Severi G, Kyrtopoulos SA, Georgiadis P, Vermeulen RC, Lund E, Vineis P, Chadeau-Hyam M (2015) Dynamics of smoking-induced genome-wide methylation changes with time since smoking cessation. Hum Mol Genet 24:2349–2359. https://doi.org/10.1093/hmg/ddu751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hecht SS (2003) Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3:733–744. https://doi.org/10.1038/nrc1190

    Article  CAS  PubMed  Google Scholar 

  • Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chen C, Goodman G, Field JK, Liloglou T, Xinarianos G, Cassidy A, McLaughlin J, Liu G, Narod S, Krokan HE, Skorpen F, Elvestad MB, Hveem K, Vatten L, Linseisen J, Clavel-Chapelon F, Vineis P, Bueno-de-Mesquita HB, Lund E, Martinez C, Bingham S, Rasmuson T, Hainaut P, Riboli E, Ahrens W, Benhamou S, Lagiou P, Trichopoulos D, Holcatova I, Merletti F, Kjaerheim K, Agudo A, Macfarlane G, Talamini R, Simonato L, Lowry R, Conway DI, Znaor A, Healy C, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452:633–637

    Article  CAS  PubMed  Google Scholar 

  • Jelinic P, Mueller JJ, Olvera N, Dao F, Scott SN, Shah R, Gao J, Schultz N, Gonen M, Soslow RA, Berger MF, Levine DA (2014) Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet 46:424–426. https://doi.org/10.1038/ng.2922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones A, Teschendorff AE, Li Q, Hayward JD, Kannan A, Mould T, West J, Zikan M, Cibula D, Fiegl H, Lee SH, Wik E, Hadwin R, Arora R, Lemech C, Turunen H, Pakarinen P, Jacobs IJ, Salvesen HB, Bagchi MK, Bagchi IC, Widschwendter M (2013) Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development. PLoS Med 10:e1001551. https://doi.org/10.1371/journal.pmed.1001551

    Article  PubMed  PubMed Central  Google Scholar 

  • Kretzmer H, Bernhart SH, Wang W, Haake A, Weniger MA, Bergmann AK, Betts MJ, Carrillo-de-Santa-Pau E, Doose G, Gutwein J, Richter J, Hovestadt V, Huang B, Rico D, Juhling F, Kolarova J, Lu Q, Otto C, Wagener R, Arnolds J, Burkhardt B, Claviez A, Drexler HG, Eberth S, Eils R, Flicek P, Haas S, Hummel M, Karsch D, Kerstens HH, Klapper W, Kreuz M, Lawerenz C, Lenze D, Loeffler M, Lopez C, MacLeod RA, Martens JH, Kulis M, Martin-Subero JI, Moller P, Nagel I, Picelli S, Vater I, Rohde M, Rosenstiel P, Rosolowski M, Russell RB, Schilhabel M, Schlesner M, Stadler PF, Szczepanowski M, Trumper L, Stunnenberg HG, Kuppers R, Ammerpohl O, Lichter P, Siebert R, Hoffmann S, Radlwimmer B, project IM-S, project B (2015) DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. Nat Genet 47:1316–1325. https://doi.org/10.1038/ng.3413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laurent L, Wong E, Li G, Huynh T, Tsirigos A, Ong CT, Low HM, Kin Sung KW, Rigoutsos I, Loring J, Wei CL (2010) Dynamic changes in the human methylome during differentiation. Genome Res 20:320–331. https://doi.org/10.1101/gr.101907.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Law JA, Jacobsen SE (2010) Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet 11:204–220. https://doi.org/10.1038/nrg2719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lawan A, Al-Harthi S, Cadalbert L, McCluskey AG, Shweash M, Grassia G, Grant A, Boyd M, Currie S, Plevin R (2011) Deletion of the dual specific phosphatase-4 (DUSP-4) gene reveals an essential non-redundant role for MAP kinase phosphatase-2 (MKP-2) in proliferation and cell survival. J Biol Chem 286:12933–12943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma Y, Li MD (2017) Establishment of a strong link between smoking and cancer pathogenesis through DNA methylation analysis. Sci Rep 7:1811. https://doi.org/10.1038/s41598-017-01856-4

    Article  PubMed  PubMed Central  Google Scholar 

  • Maccani JZ, Maccani MA (2015) Altered placental DNA methylation patterns associated with maternal smoking: current perspectives. Adv Genomics Genet 2015:205–214. https://doi.org/10.2147/AGG.S61518

    Article  PubMed  PubMed Central  Google Scholar 

  • Medina PP, Sanchez-Cespedes M (2008) Involvement of the chromatin-remodeling factor BRG1/SMARCA4 in human cancer. Epigenetics 3:64–68

    Article  PubMed  Google Scholar 

  • Medina PP, Carretero J, Fraga MF, Esteller M, Sidransky D, Sanchez-Cespedes M (2004) Genetic and epigenetic screening for gene alterations of the chromatin-remodeling factor, SMARCA4/BRG1, in lung tumors. Genes Chromosomes Cancer 41:170–177. https://doi.org/10.1002/gcc.20068

    Article  CAS  PubMed  Google Scholar 

  • Novakovic B, Ryan J, Pereira N, Boughton B, Craig JM, Saffery R (2014) Postnatal stability, tissue, and time specific effects of AHRR methylation change in response to maternal smoking in pregnancy. Epigenetics 9:377–386. https://doi.org/10.4161/epi.27248

    Article  CAS  PubMed  Google Scholar 

  • Pastrello C, Pasini E, Kotlyar M, Otasek D, Wong S, Sangrar W, Rahmati S, Jurisica I (2014) Integration, visualization and analysis of human interactome. Biochem Biophys Res Commun 445:757–773. https://doi.org/10.1016/j.bbrc.2014.01.151

    Article  CAS  PubMed  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. https://doi.org/10.1038/sj.onc.1205803

    Article  CAS  PubMed  Google Scholar 

  • Radtke F, Raj K (2003) The role of notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767. https://doi.org/10.1038/nrc1186

    Article  CAS  PubMed  Google Scholar 

  • Shenker NS, Polidoro S, van Veldhoven K, Sacerdote C, Ricceri F, Birrell MA, Belvisi MG, Brown R, Vineis P, Flanagan JM (2013) Epigenome-wide association study in the European prospective investigation into cancer and nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. Hum Mol Genet 22:843–851. https://doi.org/10.1093/hmg/dds488

    Article  CAS  PubMed  Google Scholar 

  • Sundar IK, Mullapudi N, Yao H, Spivack SD, Rahman I (2011) Lung cancer and its association with chronic obstructive pulmonary disease: update on nexus of epigenetics. Curr Opin Pulm Med 17:279–285. https://doi.org/10.1097/MCP.0b013e3283477533

    Article  PubMed  PubMed Central  Google Scholar 

  • Teschendorff AE, Jones A, Fiegl H, Sargent A, Zhuang JJ, Kitchener HC, Widschwendter M (2012) Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Med 4:24. https://doi.org/10.1186/gm323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP, Manolescu A, Thorleifsson G, Stefansson H, Ingason A, Stacey SN, Bergthorsson JT, Thorlacius S, Gudmundsson J, Jonsson T, Jakobsdottir M, Saemundsdottir J, Olafsdottir O, Gudmundsson LJ, Bjornsdottir G, Kristjansson K, Skuladottir H, Isaksson HJ, Gudbjartsson T, Jones GT, Mueller T, Gottsater A, Flex A, Aben KK, de Vegt F, Mulders PF, Isla D, Vidal MJ, Asin L, Saez B, Murillo L, Blondal T, Kolbeinsson H, Stefansson JG, Hansdottir I, Runarsdottir V, Pola R, Lindblad B, van Rij AM, Dieplinger B, Haltmayer M, Mayordomo JI, Kiemeney LA, Matthiasson SE, Oskarsson H, Tyrfingsson T, Gudbjartsson DF, Gulcher JR, Jonsson S, Thorsteinsdottir U, Kong A, Stefansson K (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452:638–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsay JJ, Tchou-Wong KM, Greenberg AK, Pass H, Rom WN (2013) Aryl hydrocarbon receptor and lung cancer. Anticancer Res 33:1247–1256

    PubMed  PubMed Central  Google Scholar 

  • Vineis P, Alavanja M, Buffler P, Fontham E, Franceschi S, Gao YT, Gupta PC, Hackshaw A, Matos E, Samet J, Sitas F, Smith J, Stayner L, Straif K, Thun MJ, Wichmann HE, Wu AH, Zaridze D, Peto R, Doll R (2004) Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst 96:99–106

    Article  CAS  PubMed  Google Scholar 

  • Waha A, Felsberg J, Hartmann W, von dem Knesebeck A, Mikeska T, Joos S, Wolter M, Koch A, Yan PS, Endl E (2010) Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells. Cancer Res 70:1689–1699

    Article  CAS  PubMed  Google Scholar 

  • WHO (2013) WHO report on the global tobacco epidemic, 2013: enforcing bans on tobacco advertising, promotion and sponsorship. World Health Organization, Geneva

    Google Scholar 

  • Yao HP, Zhou YQ, Zhang R, Wang MH (2013) MSP-RON signalling in cancer: pathogenesis and therapeutic potential. Nat Rev Cancer 13:466–481. https://doi.org/10.1038/nrc3545

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Yang R, Burwinkel B, Breitling LP, Holleczek B, Schottker B, Brenner H (2014) F2RL3 methylation in blood DNA is a strong predictor of mortality. Int J Epidemiol 43:1215–1225. https://doi.org/10.1093/ije/dyu006

    Article  PubMed  PubMed Central  Google Scholar 

  • Zudaire E, Cuesta N, Murty V, Woodson K, Adams L, Gonzalez N, Martinez A, Narayan G, Kirsch I, Franklin W, Hirsch F, Birrer M, Cuttitta F (2008) The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. J Clin Invest 118:640–650. https://doi.org/10.1172/JCI30024

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

This chapter was modified from the published work by our group in Scientific Report (Ma and Li 2017). The related contents are reused with permission.

Author information

Authors and Affiliations

  1. University of Virginia, Charlottesville, USA

    Ming D. Li

  2. Zhejiang University, Hangzhou, China

    Ming D. Li

Authors
  1. Ming D. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Li, M.D. (2018). DNA Methylation Analysis Reveals a Strong Connection Between Tobacco Smoking and Cancer Pathogenesis. In: Tobacco Smoking Addiction: Epidemiology, Genetics, Mechanisms, and Treatment. Springer, Singapore. https://doi.org/10.1007/978-981-10-7530-8_17

Download citation

Publish with us

Policies and ethics

Search

Navigation