Skip to main content

Advertisement

SpringerLink
Log in

Association of secondhand smoke exposures with DNA methylation in bladder carcinomas

  • Brief report
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Background

The association between secondhand smoke (SHS) exposure and bladder cancer is inconclusive. Epigenetic alterations in bladder tumors have been linked to primary cigarette smoking and could add to the biological plausibility of an association between SHS exposure and bladder cancer.

Hypothesis

SHS exposure is associated with DNA methylation in bladder tumors.

Methods

Using an array-based approach, we profiled DNA methylation from never smoking cases of incident bladder cancer. Analyses examined associations between individual loci’s methylation with SHS variables (exposure in adulthood, childhood, occupationally, and total exposure). A canonical pathway analysis was used to find pathways significantly associated with each SHS exposure type.

Results

There is a trend toward increased methylation of numerous CpG loci with increasing exposure to adulthood, occupational, and total SHS. Discrete associations between methylation extent of several CpG loci and SHS exposures demonstrated significantly increased methylation of these loci across all types of SHS exposure. CpGs with SHS-related methylation alterations were associated with genes in pathways involved in carcinogenesis, immune modulation, and immune signaling.

Interpretation

Exposures to SHS in adulthood, childhood, occupationally, and in total are each significantly associated with changes in DNA methylation of several CpG loci in bladder tumors, adding biological plausibility to SHS as a risk factor for bladder cancer.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. American Cancer Society (2009) Cancer facts and figures 2009. American Cancer Society, Atlanta, Ga

    Google Scholar 

  2. Parkin MP (2008) The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl 218:12–20

    Article  PubMed  Google Scholar 

  3. Karagas MR, Tosteson TD, Morris JS, Demidenko E, Mott LA, Heaney J et al (2004) Incidence of transitional cell carcinoma of the bladder and arsenic exposure in New Hampshire. Cancer Causes Control 15(5):465–472

    Article  PubMed  Google Scholar 

  4. Boffetta P (2006) Human cancer from environmental pollutants: The epidemiological evidence. Mutat Res 608(2):157–162

    PubMed  CAS  Google Scholar 

  5. Wolff EM, Liang G, Jones PA (2005) Mechanisms of disease: genetic and epigenetic alterations that drive bladder cancer. Nat Clin Pract Urol 2(10):502–510

    Article  PubMed  CAS  Google Scholar 

  6. Kaufman DS, Shipley WU, Feldman AS (2009) Bladder cancer. Lancet 374(9685):239–249

    Article  PubMed  CAS  Google Scholar 

  7. Dinney CP, McConkey DJ, Millikan RE, Wu X, Bar-Eli M, Adam L et al (2004) Focus on bladder cancer. Cancer Cell 6(2):111–116

    Article  PubMed  CAS  Google Scholar 

  8. Silverman DT, Devesa SS, Moore LL (2006) Bladder cancer. In: Schottenfeld D, Fraumeni JF Jr (eds) Cancer epidemiology and prevention. Oxford University Press, New York, NY, pp 1101–1127

    Chapter  Google Scholar 

  9. Jones PA, Ross RK (1999) Prevention of bladder cancer. N Engl J Med 340(18):1424–1426

    Article  PubMed  CAS  Google Scholar 

  10. Vineis P, Pirastu R (1997) Aromatic amines and cancer. Cancer Causes Control 8(3):346–355

    Article  PubMed  CAS  Google Scholar 

  11. Skipper PL, Tannenbaum SR, Ross RK, Yu MC (2003) Nonsmoking-related arylamine exposure and bladder cancer risk. Cancer Epidemiol Biomarkers Prev 12(6):503–507

    PubMed  CAS  Google Scholar 

  12. Anderson KE, Carmella SG, Ye M, Bliss RL, Le C, Murphy L et al (2001) Metabolites of a tobacco-specific lung carcinogen in nonsmoking women exposed to environmental tobacco smoke. J Natl Cancer Inst 93:378–381

    Article  PubMed  CAS  Google Scholar 

  13. Vineis P, Alavanja M, Garte S (2004) Dose-response relationship in tobacco-related cancers of bladder and lung: a biochemical interpretation. Int J Cancer 108:2–7

    Article  PubMed  CAS  Google Scholar 

  14. Talaska G (2003) Aromatic amines and human urinary bladder cancer: exposure sources and epidemiology. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 21(1):29–43

    PubMed  Google Scholar 

  15. Mohtashamipur E, Norpoth K, Lieder F (1987) Urinary excretion of mutagens in smokers of cigarettes with various tar and nicotine yields, black tobacco, and cigars. Cancer Lett 34:103–112

    Article  PubMed  CAS  Google Scholar 

  16. Riedel K, Scherer G, Engl J, Hagedorn HW, Tricker AR (2006) Determination of three carcinogenic aromatic amines in urine of smokers and nonsmokers. J Anal Toxicol 30(3):187–195

    PubMed  CAS  Google Scholar 

  17. Burch JD, Rohan TE, Howe GR, Risch HA, Hill GB, Steele R et al (1989) Risk of bladder cancer by source and type of tobacco exposure: a case-control study. Int J Cancer 44:622–628

    Article  PubMed  CAS  Google Scholar 

  18. Zeegers MP, Goldbohm RA, van den Brandt PA (2002) A prospective study on active and environmental tobacco smoking and bladder cancer risk (the Netherlands). Cancer Causes Control 13:83–90

    Article  PubMed  Google Scholar 

  19. Sandler DP, Everson RB, Wilcox AJ (1985) Passive smoking in adulthood and cancer risk. Am J Epidemiol 121:37–48

    PubMed  CAS  Google Scholar 

  20. Jiang X, Yuan JM, Skipper PL (2005) A case-control study of passive smoking and bladder cancer risk among lifelong nonsmokers in Los Angeles. Proc Amer Assoc Cancer Res 46:2210

    Google Scholar 

  21. Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6(2):107–116

    Article  PubMed  CAS  Google Scholar 

  22. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428

    PubMed  CAS  Google Scholar 

  23. Marsit CJ, Karagas MR, Danaee H, Liu M, Andrew A, Schned A et al (2006) Carcinogen exposure and gene promoter hypermethylation in bladder cancer. Carcinogenesis 27(1):112–116

    Article  PubMed  CAS  Google Scholar 

  24. Marsit CJ, Houseman EA, Schned AR, Karagas MR, Kelsey KT (2007) Promoter hypermethylation is associated with current smoking, age, gender and survival in bladder cancer. Carcinogenesis 28(8):1745–1751

    Article  PubMed  CAS  Google Scholar 

  25. Baris D, Karagas MR, Verrill C, Johnson A, Andrew AS, Marsit CJ et al (2009) A case-control study of smoking and bladder cancer risk: emergent patterns over time. J Natl Cancer Inst 101(22):1553–1561

    Article  PubMed  Google Scholar 

  26. Karagas MR, Tosteson TD, Blum J, Morris JS, Baron JA, Klaue B (1998) Design of an epidemiologic study of drinking water arsenic exposure and skin and bladder cancer risk in a US population. Environ Health Perspect 106(Suppl 4):1047–1050

    Article  PubMed  Google Scholar 

  27. Marsit CJ, Karagas MR, Andrew A, Liu M, Danaee H, Schned AR et al (2005) Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res 65(16):7081–7085

    Article  PubMed  CAS  Google Scholar 

  28. Bibikova M, Lin Z, Zhou L, Chudin E, Garcia EW, Wu B et al (2006) High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16(3):383–393

    Article  PubMed  CAS  Google Scholar 

  29. Christensen BC, Kelsey KT, Zheng S, Houseman EA, Marsit CJ, Wrensch MR et al (2010) Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake. PLoS Genet 6(7):e1001043

    Article  PubMed  Google Scholar 

  30. Marsit CJ, Houseman EA, Christensen BC, Gagne L, Wrensch MR, Nelson HH et al (2010) Identification of methylated genes associated with aggressive bladder cancer. PLoS One 5(8):e12334

    Article  PubMed  Google Scholar 

  31. Hsiung DT, Marsit CJ, Houseman EA, Eddy K, Furniss CS, McClean MD et al (2007) Global DNA methylation level in whole blood as a biomarker in head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 16(1):108–114

    Article  PubMed  Google Scholar 

  32. Storey J, Taylor J, Siegmund D (2004) Strong control, conservative point estimation and simulteanous conservative consistency of false discovery rates: a unified approach. J Royal Stat Soc Series B 66(Pt 1):187–205

    Article  Google Scholar 

  33. Ingenuity Pathways Analysis Software (2011) Ingenuity Systems Inc. http://www.ingenuity.com/. Accessed 13 Oct 2010

  34. Schlott T, Quentin T, Korabiowska M, Budd B, Kunze E (2004) Alteration of the MDM2–p73-P14ARF pathway related to tumour progression during urinary bladder carcinogenesis. Int J Mol Med 14(5):825–836

    PubMed  CAS  Google Scholar 

  35. Schayek H, Bentov I, Sun S, Plymate SR, Werner H (2010) Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene. Exp Cell Res 316(9):1479–1488

    Article  PubMed  CAS  Google Scholar 

  36. Huang Z, Wen Y, Shandilya R, Marks JR, Berchuck A, Murphy SK (2006) High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer. Nucleic Acids Res 34(2):555–563

    Article  PubMed  CAS  Google Scholar 

  37. Hinoue T, Weisenberger DJ, Pan F, Campan M, Kim M, Young J (2009) Analysis of the association between CIMP and BRAF in colorectal cancer by DNA methylation profiling. PLoS One 4(12):e8357

    Article  PubMed  Google Scholar 

  38. Alazzouzi H, Davalos V, Kokko A, Domingo E, Woerner SM, Wilson AJ et al (2005) Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. Cancer Res 65(22):10170–10173

    Article  PubMed  CAS  Google Scholar 

  39. Kuang SQ, Bai H, Fang ZH, Lopez G, Yang H, Tong W et al (2010) Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia. Blood 115(12):2412–2419

    Article  PubMed  CAS  Google Scholar 

  40. Sharma G, Mirza S, Parshad R, Srivastava A, Gupta SD, Pandya P et al (2010) Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients. Life Sci 87(3–4):83–91

    Article  PubMed  CAS  Google Scholar 

  41. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003

    Article  PubMed  CAS  Google Scholar 

  42. Kikuchi R, Tsuda H, Kanai Y, Kasamatsu T, Sengoku K, Hirohashi S et al (2007) Promoter hypermethylation contributes to frequent inactivation of a putative conditional tumor suppressor gene connective tissue growth factor in ovarian cancer. Cancer Res 67(15):7095–7105

    Article  PubMed  CAS  Google Scholar 

  43. Aaronson DS, Horvath CM (2002) A road map for those who don’t know JAK-STAT. Science 296(5573):1653–1655

    Article  PubMed  CAS  Google Scholar 

  44. Sokol CL, Barton GM, Farr AG, Medzhitov R (2008) A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol 9(3):310–318

    Article  PubMed  CAS  Google Scholar 

  45. Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS et al (1986) Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell 47(1):3–10

    Article  PubMed  CAS  Google Scholar 

  46. Maeda A, Maeda T, Liang Y, Yenerel M, Saperstein DA (2006) Effects of cytotoxic T lymphocyte antigen 4 (CTLA4) signaling and locally applied steroid on retinal dysfunction by recoverin, cancer-associated retinopathy antigen. Mol Vis 12:885–891

    PubMed  CAS  Google Scholar 

  47. Govers C, Sebestyén Z, Coccoris M, Willemsen RA, Debets R (2010) T cell receptor gene therapy: strategies for optimizing transgenic TCR pairing. Trends Mol Med 16(2):77–87

    Article  PubMed  CAS  Google Scholar 

  48. Tóvári J, Pirker R, Tímár J, Ostoros G, Kovács G, Döme B (2008) Erythropoietin in cancer: an update. Curr Mol Med 8(6):481–491

    Article  PubMed  Google Scholar 

  49. Roberts OL, Holmes K, Müller J, Cross DA, Cross MJ (2009) ERK5 and the regulation of endothelial cell function. Biochem Soc Trans 37(Pt 6):1254–1259

    Article  PubMed  CAS  Google Scholar 

  50. Zhao Y, Chen X, Cai L, Yang Y, Sui G, Fu S (2010) Angiotensin II/Angiotensin II type I receptor (AT1R) signaling promotes MCF-7 breast cancer cells survival via PI3-kinase/Akt pathway. J Cell Physiol 225(1):168–173

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Dr. Dominique Michaud for helpful comments and suggestions for this work. This work was supported by the Flight Attendant Medical Research Institute (YCSA 052341 to C.J.M.) and the National Institutes of Health (R01CA121147, and P42ES007373 and R01CA057494).

Conflicts of interest

The authors declared no conflicts of interest and no financial disclosures.

Author information

Authors and Affiliations

  1. Department of Community Health Center for Environmental Health and Technology, Brown University, Providence, RI, USA

    Charlotte S. Wilhelm-Benartzi, Brock C. Christensen, Devin C. Koestler, E. Andres Houseman, Karl T. Kelsey & Carmen J. Marsit

  2. Department of Pathology and Laboratory Medicine, Brown University, Box G-E537, Providence, RI, 02912, USA

    Brock C. Christensen, Karl T. Kelsey & Carmen J. Marsit

  3. Department of Pathology, Dartmouth Medical School, Lebanon, NH, USA

    Alan R. Schned

  4. Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH, USA

    Margaret R. Karagas

Authors
  1. Charlotte S. Wilhelm-Benartzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brock C. Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Devin C. Koestler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Andres Houseman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alan R. Schned
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Margaret R. Karagas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karl T. Kelsey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carmen J. Marsit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carmen J. Marsit.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 237 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilhelm-Benartzi, C.S., Christensen, B.C., Koestler, D.C. et al. Association of secondhand smoke exposures with DNA methylation in bladder carcinomas. Cancer Causes Control 22, 1205–1213 (2011). https://doi.org/10.1007/s10552-011-9788-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-011-9788-6

Keywords

Search

Navigation