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Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study

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Abstract

Background

Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case–control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case–control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.

Methods

In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.

Results

Individuals with low LINE-1 methylation (<median) had a 3.0-fold (95%CI 1.3–6.9) increased incidence of all cancers combined. LINE-1 and Alu methylation were not significantly associated with cancer prevalence at baseline (all cancers combined). However, individuals with low LINE-1 methylation (<median) had a 3.2-fold (95% CI 1.4–7.5) higher prevalence of lung cancer. Individuals with low LINE-1 or Alu methylation (<median) had increased cancer mortality (HR = 3.2, 95%CI 1.3–7.9 for LINE-1; HR = 2.5, 95%CI 1.1–5.8 for Alu).

Conclusion

These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.

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References

  1. Ohgane J, Yagi S, Shiota K (2008) Epigenetics: the DNA methylation profile of tissue-dependent and differentially methylated regions in cells. Placenta 29:S29–S35

    PubMed  Google Scholar 

  2. Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921

    Article  CAS  PubMed  Google Scholar 

  3. Wilson AS, Power BE, Molloy PL (2007) DNA hypomethylation and human diseases. Biochim Biophys Acta 1775:138–162

    CAS  PubMed  Google Scholar 

  4. Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32:e38

    Article  PubMed  Google Scholar 

  5. Gluckman PD, Hanson MA, Cooper C, Thornburg KL (2008) Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359:61–73

    Article  CAS  PubMed  Google Scholar 

  6. Hsieh CL (2000) Dynamics of DNA methylation pattern. Curr Opin Genet Dev 10:224–228

    Article  CAS  PubMed  Google Scholar 

  7. Das PM, Singal R (2004) DNA methylation and cancer. J Clin Oncol 22:4632–4642

    Article  CAS  PubMed  Google Scholar 

  8. Moore LE, Pfeiffer RM, Poscablo C et al (2008) Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case-control study. Lancet Oncol 9:359–366

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Pufulete M, Al-Ghnaniem R, Leather AJ et al (2003) Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124:1240–1248

    Article  CAS  PubMed  Google Scholar 

  11. Choi JY, James SR, Link PA et al (2009) Association between global DNA hypomethylation in leukocytes and risk of breast cancer. Carcinogenesis 30:1889–1897

    Article  CAS  PubMed  Google Scholar 

  12. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7:11–20

    Article  CAS  PubMed  Google Scholar 

  13. Lelbach A, Muzes G, Feher J (2007) Current perspectives of catabolic mediators of cancer cachexia. Med Sci Monit 13:RA168-173

    Google Scholar 

  14. Gaudet F, Hodgson JG, Eden A et al (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492

    Article  CAS  PubMed  Google Scholar 

  15. Wilson MJ, Shivapurkar N, Poirier LA (1984) Hypomethylation of hepatic nuclear DNA in rats fed with a carcinogenic methyl-deficient diet. Biochem J 218:987–990

    CAS  PubMed  Google Scholar 

  16. Thomas GA, Williams ED (1992) Production of thyroid tumours in mice by demethylating agents. Carcinogenesis 13:1039–1042

    Article  CAS  PubMed  Google Scholar 

  17. 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 Biomarkers Prev 17:966–971

    Article  CAS  PubMed  Google Scholar 

  18. Tangkijvanich P, Hourpai N, Rattanatanyong P, Wisedopas N, Mahachai V, Mutirangura A (2007) Serum LINE-1 hypomethylation as a potential prognostic marker for hepatocellular carcinoma. Clin Chim Acta 379:127–133

    Article  CAS  PubMed  Google Scholar 

  19. Bell B, Rose C, Damon A (1972) The normative aging study: an interdisciplinary and longitudinal study of health and aging. Int J Aging Hum Dev 3:5–17

    Article  Google Scholar 

  20. Bollati V, Baccarelli A, Hou L et al (2007) Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res 67:876–880

    Article  CAS  PubMed  Google Scholar 

  21. Tarantini L, Bonzini M, Apostoli P et al (2009) Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect 117:217–222

    CAS  PubMed  Google Scholar 

  22. Jacob RA, Gretz DM, Taylor PC et al (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J Nutr 128:1204–1212

    CAS  PubMed  Google Scholar 

  23. Williams KT, Garrow TA, Schalinske KL (2008) Type I diabetes leads to tissue-specific DNA hypomethylation in male rats. J Nutr 138:2064–2069

    Article  CAS  PubMed  Google Scholar 

  24. Baccarelli A, Wright RO, Bollati V et al (2009) Low blood DNA methylation determines higher risk and mortality from ischemic heart disease and stroke among elderly individuals. Circulation 119:E281

    Article  Google Scholar 

  25. Lim U, Flood A, Choi SW et al (2008) Genomic methylation of leukocyte DNA in relation to colorectal adenoma among asymptomatic women. Gastroenterology 134:47–55

    Article  PubMed  Google Scholar 

  26. Bollati V, Schwartz J, Wright R et al (2009) Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev 130:234–239

    Article  CAS  PubMed  Google Scholar 

  27. Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD (2009) Prenatal Tobacco Smoke Exposure Affects Global and Gene-Specific DNA Methylation. Am J Respir Crit Care Med 180:462–467

    Article  CAS  PubMed  Google Scholar 

  28. Rusiecki JA, Baccarelli A, Bollati V, Tarantini L, Moore LE, Bonefeld-Jorgensen EC (2008) Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit. Environ Health Perspect 116:1547–1552

    Article  CAS  PubMed  Google Scholar 

  29. Hillemacher T, Frieling H, Moskau S et al (2008) Global DNA methylation is influenced by smoking behaviour. Eur Neuropsychopharmacol 18:295–298

    Article  CAS  PubMed  Google Scholar 

  30. Bjornsson HT, Sigurdsson MI, Fallin MD et al (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299:2877–2883

    Article  CAS  PubMed  Google Scholar 

  31. Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7:21–33

    Article  CAS  PubMed  Google Scholar 

  32. Steinhoff C, Schulz WA (2003) Transcriptional regulation of the human LINE-1 retrotransposon L1.2B. Mol Genet Genomics 270:394–402

    Article  CAS  PubMed  Google Scholar 

  33. Babushok DV, Kazazian HH Jr (2007) Progress in understanding the biology of the human mutagen LINE-1. Hum Mutat 28:527–539

    Article  CAS  PubMed  Google Scholar 

  34. Lin CH, Hsieh SY, Sheen IS et al (2001) Genome-wide hypomethylation in hepatocellular carcinogenesis. Cancer Res 61:4238–4243

    CAS  PubMed  Google Scholar 

  35. Soares J, Pinto AE, Cunha CV et al (1999) Global DNA hypomethylation in breast carcinoma: correlation with prognostic factors and tumor progression. Cancer 85:112–118

    Article  CAS  PubMed  Google Scholar 

  36. Smith IM, Mydlarz WK, Mithani SK, Califano JA (2007) DNA global hypomethylation in squamous cell head and neck cancer associated with smoking, alcohol consumption and stage. Int J Cancer 121:1724–1728

    Article  CAS  PubMed  Google Scholar 

  37. Ogino S, Nosho K, Kirkner GJ et al (2008) A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J Natl Cancer Inst 100:1734–1738

    Article  CAS  PubMed  Google Scholar 

  38. Cho NY, Kim BH, Choi M et al (2007) Hypermethylation of CpG island loci and hypomethylation of LINE-1 and Alu repeats in prostate adenocarcinoma and their relationship to clinicopathological features. J Pathol 211:269–277

    Article  CAS  PubMed  Google Scholar 

  39. Widschwendter M, Apostolidou S, Raum E et al (2008) Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study. PLoS One 3:e2656

    Article  PubMed  Google Scholar 

  40. Zhu ZZ, Hou L, Bollati V et al (2010) Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis. Int J Epidemiol doi:10.1093/ije/dyq154

  41. Terry MB, Ferris JS, Pilsner R et al (2008) Genomic DNA methylation among women in a multiethnic New York City birth cohort. Cancer Epidemiol Biomarkers Prev 17:2306–2310

    Article  CAS  PubMed  Google Scholar 

  42. El-Maarri O, Becker T, Junen J et al (2007) Gender specific differences in levels of DNA methylation at selected loci from human total blood: a tendency toward higher methylation levels in males. Hum Genet 122:505–514

    Article  CAS  PubMed  Google Scholar 

  43. Choi IS, Estecio MR, Nagano Y et al (2007) Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors). Mod Pathol 20:802–810

    Article  CAS  PubMed  Google Scholar 

  44. Li TH, Schmid CW (2001) Differential stress induction of individual Alu loci: implications for transcription and retrotransposition. Gene 276:135–141

    Article  CAS  PubMed  Google Scholar 

  45. Hou L, Wang H, Sartori S et al (2010) Blood leukocyte DNA hypomethylation and gastric cancer risk in a high-risk Polish population. Int J Cancer 127:1866–1874

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. von Sternberg RM, Novick GE, Gao GP, Herrera RJ (1992) Genome canalization: the coevolution of transposable and interspersed repetitive elements with single copy DNA. Genetica 86:215–246

    Article  Google Scholar 

  48. Biemont C, Vieira C (2006) Genetics: junk DNA as an evolutionary force. Nature 443:521–524

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Institute of Environmental Health Sciences grants ES015172-01; New Investigator funding from the HSPH-NIEHS Center for Environmental Health (ES000002); Environmental Protection Agency grants R83241601 and R827353; and Italian Association for Cancer Research (AIRC-6016). The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC).

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Authors and Affiliations

  1. Center of Molecular and Genetic Epidemiology, Department of Environmental and Occupational Health, Università degli Studi di Milano and IRCCS Maggiore Policlinico Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy

    Zhong-Zheng Zhu, Letizia Tarantini, Valentina Bollati & Andrea Baccarelli

  2. Department of Oncology, No.3 People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Zhong-Zheng Zhu

  3. VA Normative Aging Study, Veterans Affairs Boston Healthcare System and the Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    David Sparrow & Pantel Vokonas

  4. Department of Preventive Medicine & Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Lifang Hou

  5. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Augusto A. Litonjua & Robert O. Wright

  6. Exposure Epidemiology and Risk Program, Harvard School of Public Health, Landmark Center, Suite 415, 401 Park Drive, Boston, MA, 02215, USA

    Antonella Zanobetti, Robert O. Wright, Andrea Baccarelli & Joel Schwartz

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  1. Zhong-Zheng Zhu
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  2. David Sparrow
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Correspondence to Joel Schwartz.

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Zhu, ZZ., Sparrow, D., Hou, L. et al. Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study. Cancer Causes Control 22, 437–447 (2011). https://doi.org/10.1007/s10552-010-9715-2

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  • DOI: https://doi.org/10.1007/s10552-010-9715-2

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