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Blood-Derived DNA Methylation Markers of Cancer Risk

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Book cover Epigenetic Alterations in Oncogenesis

Part of the book series: Advances in Experimental Medicine and Biology ((volume 754))

Abstract

The importance of somatic epigenetic alterations in tissues targeted for carcinogenesis is now well recognized and considered a key molecular step in the development of a tumor. Particularly, alteration of gene-specific and genomic DNA methylation has been extensively characterized in tumors, and has become an attractive biomarker of risk due to its specificity and stability in human samples. It also is clear that tumors do not develop as isolated phenomenon in their target tissue, but instead result from altered processes affecting not only the surrounding cells and tissues, but other organ systems, including the immune system. Thus, alterations to DNA methylation profiles detectable in peripheral blood may be useful not only in understanding the carcinogenic process and response to environmental insults, but can also provide critical insights in a systems biological view of tumorigenesis. Research to date has generally focused on how environmental exposures alter genomic DNA methylation content in peripheral blood. More recent work has begun to translate these findings to clinically useful endpoints, by defining the relationship between DNA methylation alterations and cancer risk. This chapter highlights the existing research linking the environment, blood-derived DNA methylation alterations, and cancer risk, and points out how these epigenetic alterations may be contributing fundamentally to carcinogenesis.

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References

  1. Alexander RP, Fang G et al (2010) Annotating non-coding regions of the genome. Nat Rev Genet 11(8):559–571

    Article  PubMed  CAS  Google Scholar 

  2. Ally MS, Al-Ghnaniem R et al (2009) The relationship between gene-specific DNA methylation in leukocytes and normal colorectal mucosa in subjects with and without colorectal tumors. Cancer Epidemiol Biomarkers Prev 18(3):922–928

    Article  PubMed  CAS  Google Scholar 

  3. Al-Moghrabi N, Al-Qasem AJ et al (2011) Methylation-related mutations in the BRCA1 promoter in peripheral blood cells from cancer-free women. Int J Oncol 39(1):129–135

    PubMed  CAS  Google Scholar 

  4. Baccarelli A, Wright RO et al (2009) Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med 179(7):572–578

    Article  PubMed  CAS  Google Scholar 

  5. Barker DJ (2004) Developmental origins of adult health and disease. J Epidemiol Community Health 58(2):114–115

    Article  PubMed  CAS  Google Scholar 

  6. Barker DJ (2004) The developmental origins of well-being. Philos Trans R Soc Lond B Biol Sci 359(1449):1359–1366

    Article  PubMed  CAS  Google Scholar 

  7. Bennett KL, Mester J et al (2010) Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA 304(24):2724–2731

    Article  PubMed  CAS  Google Scholar 

  8. Bibikova M, Lin Z et al (2006) High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16(3):383–393

    Article  PubMed  CAS  Google Scholar 

  9. Birgisdottir V, Stefansson OA et al (2006) Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast cancer research: BCR 8(4):R38

    Article  PubMed  Google Scholar 

  10. Bollati V, Baccarelli A et al (2007) Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res 67(3):876–880

    Article  PubMed  CAS  Google Scholar 

  11. Bosviel R, Michard E et al (2011) Peripheral blood DNA methylation detected in the BRCA1 or BRCA2 promoter for sporadic ovarian cancer patients and controls. Clin Chim Acta 412(15–16):1472–1475

    Article  PubMed  CAS  Google Scholar 

  12. Butcher DT, Rodenhiser DI (2007) Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours. Eur J Cancer 43(1):210–219

    Article  PubMed  CAS  Google Scholar 

  13. Cash HL, Tao L et al (2011) LINE-1 hypomethylation is associated with bladder cancer risk among nonsmoking Chinese. Int J Cancer 130(5):1151–1159

    Article  PubMed  Google Scholar 

  14. Chan TL, Yuen ST et al (2006) Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 38(10):1178–1183

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. Christensen BC, Houseman EA et al (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5(8):e1000602

    Article  PubMed  Google Scholar 

  17. Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10(10):691–703

    Article  PubMed  CAS  Google Scholar 

  18. Deininger PL, Batzer MA (1999) Alu repeats and human disease. Mol Genet Metab 67(3): 183–193

    Article  PubMed  CAS  Google Scholar 

  19. Dewannieux M, Esnault C et al (2003) LINE-mediated retrotransposition of marked Alu sequences. Nat Genet 35(1):41–48

    Article  PubMed  CAS  Google Scholar 

  20. Dobrovic A, Kristensen LS (2009) DNA methylation, epimutations and cancer predisposition. Int J Biochem Cell Biol 41(1):34–39

    Article  PubMed  CAS  Google Scholar 

  21. Eads CA, Danenberg KD et al (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28(8):E32

    Article  PubMed  CAS  Google Scholar 

  22. Flanagan JM, Munoz-Alegre M et al (2009) Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. Hum Mol Genet 18(7):1332–1342

    Article  PubMed  CAS  Google Scholar 

  23. Florl AR, Lower R et al (1999) DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas. Br J Cancer 80(9):1312–1321

    Article  PubMed  CAS  Google Scholar 

  24. Fraga MF, Ballestar E et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102(30):10604–10609

    Article  PubMed  CAS  Google Scholar 

  25. Futreal PA, Liu Q et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266(5182):120–122

    Article  PubMed  CAS  Google Scholar 

  26. Gama-Sosa MA, Wang RY et al (1983) The 5-methylcytosine content of highly repeated sequences in human DNA. Nucleic Acids Res 11(10):3087–3095

    Article  PubMed  CAS  Google Scholar 

  27. Gaudet F, Hodgson JG et al (2003) Induction of tumors in mice by genomic hypomethylation. Science 300(5618):489–492

    Article  PubMed  CAS  Google Scholar 

  28. Gicquel C, Rossignol S et al (2005) Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 37(9):1003–1007

    Article  PubMed  CAS  Google Scholar 

  29. Hajkova P, Erhardt S et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117(1–2):15–23

    Article  PubMed  CAS  Google Scholar 

  30. Herman JG, Graff JR et al (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93(18):9821–9826

    Article  PubMed  CAS  Google Scholar 

  31. Hitchins MP (2010) Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. Adv Genet 70:201–243

    Article  PubMed  CAS  Google Scholar 

  32. Hitchins M, Williams R et al (2005) MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 129(5):1392–1399

    Article  PubMed  CAS  Google Scholar 

  33. Hitchins MP, Wong JJ et al (2007) Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 356(7):697–705

    Article  PubMed  CAS  Google Scholar 

  34. Hitchins M, Owens S et al (2011) Identification of new cases of early-onset colorectal cancer with an MLH1 epimutation in an ethnically diverse South African cohort(dagger). Clin Genet 80(5):428–434

    Article  PubMed  CAS  Google Scholar 

  35. Hou L, Wang H et al (2010) Blood leukocyte DNA hypomethylation and gastric cancer risk in a high-risk Polish population. Int J Cancer 127(8):1866–1874

    Article  PubMed  CAS  Google Scholar 

  36. Hsiung DT, Marsit CJ 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 

  37. Iwamoto T, Yamamoto N et al (2011) BRCA1 promoter methylation in peripheral blood cells is associated with increased risk of breast cancer with BRCA1 promoter methylation. Breast Cancer Res Treat 129(1):69–77

    Article  PubMed  CAS  Google Scholar 

  38. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21(2):163–167

    Article  PubMed  CAS  Google Scholar 

  39. Jordan IK, Rogozin IB et al (2003) Origin of a substantial fraction of human regulatory sequences from transposable elements. Trends Genet 19(2):68–72

    Article  PubMed  CAS  Google Scholar 

  40. Koestler DC, Marsit CJ et al (2010) Semi-supervised recursively partitioned mixture models for identifying cancer subtypes. Bioinformatics 26(20):2578–2585

    Article  PubMed  CAS  Google Scholar 

  41. Kolomietz E, Meyn MS et al (2002) The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors. Genes Chromosomes Cancer 35(2):97–112

    Article  PubMed  CAS  Google Scholar 

  42. Lancaster JM, Wooster R et al (1996) BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13(2):238–240

    Article  PubMed  CAS  Google Scholar 

  43. Lander ES, Linton LM et al (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921

    Article  PubMed  CAS  Google Scholar 

  44. Langevin SM, Koestler DC et al (2012) Peripheral blood DNA methylation profiles are predictive of head and neck squamous cell carcinoma: an epigenome-wide association study. Epigenetics 7(3):291–299

    Article  PubMed  CAS  Google Scholar 

  45. Lee J, Inoue K et al (2002) Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 129(8):1807–1817

    PubMed  CAS  Google Scholar 

  46. Li W, Deng J et al (2010) Association of 5′-CpG island hypermethylation of the FHIT gene with lung cancer in southern-central Chinese population. Cancer Biol Ther 10(10):997–1000

    Article  PubMed  CAS  Google Scholar 

  47. Lim U, Flood A et al (2008) Genomic methylation of leukocyte DNA in relation to colorectal adenoma among asymptomatic women. Gastroenterology 134(1):47–55

    Article  PubMed  Google Scholar 

  48. Liu Z, Zhao J et al (2008) CpG island methylator phenotype involving tumor suppressor genes located on chromosome 3p in non-small cell lung cancer. Lung Cancer 62(1):15–22

    Article  PubMed  CAS  Google Scholar 

  49. Liu Z, Li W et al (2010) CpG island methylator phenotype involving chromosome 3p confers an increased risk of non-small cell lung cancer. J Thorac Oncol 5(6):790–797

    Article  PubMed  Google Scholar 

  50. Marsit CJ, Koestler DC et al (2011) DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer. J Clin Oncol 29(9): 1133–1139

    Article  PubMed  Google Scholar 

  51. McCarthy MI, Hirschhorn JN (2008) Genome-wide association studies: potential next steps on a genetic journey. Hum Mol Genet 17(R2):R156–R165

    Article  PubMed  CAS  Google Scholar 

  52. McKay JD, Truong T et al (2011) A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet 7(3):e1001333

    Article  PubMed  CAS  Google Scholar 

  53. Menendez L, Benigno BB et al (2004) L1 and HERV-W retrotransposons are hypomethylated in human ovarian carcinomas. Mol Cancer 3:12

    Article  PubMed  Google Scholar 

  54. Moore LE, Pfeiffer RM 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(4):359–366

    Article  PubMed  CAS  Google Scholar 

  55. Morak M, Schackert HK et al (2008) Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. Eur J Hum Genet 16(7):804–811

    Article  PubMed  CAS  Google Scholar 

  56. Nelson HH, Marsit CJ et al (2011) “Global methylation” in exposure biology and translational medical science. Environ Health Perspect 119(11):1528–1533

    Article  PubMed  CAS  Google Scholar 

  57. Netchine I, Rossignol S et al (2007) 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab 92(8):3148–3154

    Article  PubMed  CAS  Google Scholar 

  58. Pavanello S, Bollati V et al (2009) Global and gene-specific promoter methylation changes are related to anti-B[a]PDE-DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon-exposed individuals. Int J Cancer 125(7):1692–1697

    Article  PubMed  CAS  Google Scholar 

  59. Pedersen KS, Bamlet WR et al (2011) Leukocyte DNA methylation signature differentiates pancreatic cancer patients from healthy controls. PLoS One 6(3):e18223

    Article  PubMed  CAS  Google Scholar 

  60. Pufulete M, Al-Ghnaniem R et al (2003) Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124(5): 1240–1248

    Article  PubMed  CAS  Google Scholar 

  61. Roupret M, Hupertan V et al (2008) Promoter hypermethylation in circulating blood cells identifies prostate cancer progression. Int J Cancer 122(4):952–956

    Article  PubMed  CAS  Google Scholar 

  62. Rusiecki JA, Baccarelli A et al (2008) Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit. Environ Health Perspect 116(11): 1547–1552

    Article  PubMed  CAS  Google Scholar 

  63. Sano H, Imokawa M et al (1988) Detection of heavy methylation in human repetitive DNA subsets by a monoclonal antibody against 5-methylcytosine. Biochim Biophys Acta 951(1): 157–165

    Article  PubMed  CAS  Google Scholar 

  64. Snell C, Krypuy M et al (2008) BRCA1 promoter methylation in peripheral blood DNA of mutation negative familial breast cancer patients with a BRCA1 tumour phenotype. Breast Cancer Res 10(1):R12

    Article  PubMed  Google Scholar 

  65. Steenman MJ, Rainier S et al (1994) Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms’ tumour. Nat Genet 7(3):433–439

    Article  PubMed  CAS  Google Scholar 

  66. Suter CM, Martin DI et al (2004) Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 36(5):497–501

    Article  PubMed  CAS  Google Scholar 

  67. Suter CM, Martin DI et al (2004) Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue. Int J Colorectal Dis 19(2):95–101

    Article  PubMed  Google Scholar 

  68. Tarantini L, Bonzini M et al (2009) Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect 117(2):217–222

    PubMed  CAS  Google Scholar 

  69. Teschendorff AE, Menon U et al (2009) An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One 4(12):e8274

    Article  PubMed  Google Scholar 

  70. Thompson ME, Jensen RA et al (1995) Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9(4):444–450

    Article  PubMed  CAS  Google Scholar 

  71. Ting DT, Lipson D et al (2011) Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers. Science 331(6017):593–596

    Article  PubMed  CAS  Google Scholar 

  72. Vineis P, Chuang SC et al (2011) DNA methylation changes associated with cancer risk factors and blood levels of vitamin metabolites in a prospective study. Epigenetics 6(2):195–201

    Article  PubMed  CAS  Google Scholar 

  73. Wang L, Aakre JA et al (2010) Methylation markers for small cell lung cancer in peripheral blood leukocyte DNA. J Thorac Oncol 5(6):778–785

    Article  PubMed  Google Scholar 

  74. Weisenberger DJ, Campan M et al (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33(21):6823–6836

    Article  PubMed  CAS  Google Scholar 

  75. Widschwendter M, Apostolidou S et al (2008) Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study. PLoS One 3(7):e2656

    Article  PubMed  Google Scholar 

  76. Wilhelm CS, Kelsey KT et al (2010) Implications of LINE1 methylation for bladder cancer risk in women. Clin Cancer Res 16(5):1682–1689

    Article  PubMed  CAS  Google Scholar 

  77. Wong IH, Lo YM et al (2000) Frequent p15 promoter methylation in tumor and peripheral blood from hepatocellular carcinoma patients. Clin Cancer Res 6(9):3516–3521

    PubMed  CAS  Google Scholar 

  78. Wong EM, Southey MC et al (2011) Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev Res (Phila) 4(1):23–33

    Article  CAS  Google Scholar 

  79. Wu HC, Delgado-Cruzata L et al (2011) Global methylation profiles in DNA from different blood cell types. Epigenetics 6(1):76–85

    Article  PubMed  CAS  Google Scholar 

  80. Yang AS, Estecio MR et al (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32(3):e38

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Dartmouth Medical School, 7650 Remsen, Hanover, NH, 03755, USA

    Carmen Marsit

  2. Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Dartmouth Medical School, 7650 Remsen, Hanover, NH, 03755, USA

    Carmen Marsit & Brock Christensen

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  1. Carmen Marsit
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  2. Brock Christensen
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Correspondence to Carmen Marsit .

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Editors and Affiliations

  1. University of Nebraska Medical Center, Eppley Institute for Research in Cancer, 985950 Nebraska Medical Center, Omaha, 68198, Nebraska, USA

    Adam R. Karpf

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Marsit, C., Christensen, B. (2013). Blood-Derived DNA Methylation Markers of Cancer Risk. In: Karpf, A. (eds) Epigenetic Alterations in Oncogenesis. Advances in Experimental Medicine and Biology, vol 754. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9967-2_12

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