Epigenetic Epidemiology for Cancer Risk: Harnessing Germline Epigenetic Variation

Part of the Methods in Molecular Biology book series (MIMB, volume 863)


Genetic epidemiology aims to use the natural variation in the genome, namely single nucleotide polymorphisms and copy number variants to look for associations between particular genotypes and disease risk or prognosis. Recent work is now aiming to look further into the genome at the natural variation present in the epigenome, in DNA methylation as well as histone modifications, which both regulate gene expression. Epigenetic epidemiology aims to address the same questions about disease risk and prognosis using the normal epigenetic variability. Some examples of rare “epimutations” that can be detected in peripheral blood DNA have been reported in the genes MLH1, MSH2 and IGF2. Other studies have reported increased cancer risk with skewed distributions of the normal pattern in cancer cases compared to controls, showing the promise of harnessing the normal variation in the epigenome. However, some confounding factors need to be considered including the relationship between the epigenome and increasing age and tissue heterogeneity. Future studies using genome-wide approaches will likely find many more novel epigenetic biomarkers for cancer risk and prognosis.

Key words

Epigenetic Methylation Cancer risk Breast cancer Peripheral blood 


  1. 1.
    Gail, M.H., Brinton, L.A., Byar, D.P., Corle, D.K., Green, S.B., Schairer, C., and Mulvihill, J.J. (1989) Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81, 1879–1886.PubMedCrossRefGoogle Scholar
  2. 2.
    Amir, E., Evans, D.G., Shenton, A., Lalloo, F., Moran, A., Boggis, C., Wilson, M., and Howell, A. (2003) Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme. J Med Genet 40, 807–814.PubMedCrossRefGoogle Scholar
  3. 3.
    Varghese, J.S., and Easton, D.F. (2010) Genome-wide association studies in common cancers—what have we learnt? Curr Opin Genet Dev 20, 201–209.PubMedCrossRefGoogle Scholar
  4. 4.
    Richards, E.J. (2006) Inherited epigenetic variation—revisiting soft inheritance. Nat Rev Genet 7, 395–401.PubMedCrossRefGoogle Scholar
  5. 5.
    Hitchins, M.P. and Ward, R.L. (2009) Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. Journal of Medical Genetics 46, 793–802.PubMedCrossRefGoogle Scholar
  6. 6.
    Hesson, L.B., Hitchins, M.P., and Ward, R.L. (2010) Epimutations and cancer predisposition: importance and mechanisms. Curr Opin Genet Dev 20, 290–298.PubMedCrossRefGoogle Scholar
  7. 7.
    Morgan, H.D., Sutherland, H.G., Martin, D.I., and Whitelaw, E. (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23, 314–318.PubMedCrossRefGoogle Scholar
  8. 8.
    Rakyan, V.K., Chong, S., Champ, M.E., Cuthbert, P.C., Morgan, H.D., Luu, K.V., and Whitelaw, E. (2003) Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci U S A 100, 2538–2543.PubMedCrossRefGoogle Scholar
  9. 9.
    Reik, W., Constancia, M., Dean, W., Davies, K., Bowden, L., Murrell, A., Feil, R., Walter, J., and Kelsey, G. (2000) Igf2 imprinting in development and disease. Int J Dev Biol 44, 145–150.PubMedGoogle Scholar
  10. 10.
    Feinberg, A.P., Kalikin, L.M., Johnson, L.A., and Thompson, J.S. (1994) Loss of imprinting in human cancer. Cold Spring Harb. Sym. 59, 357–364.CrossRefGoogle Scholar
  11. 11.
    Cruz-Correa, M., Cui, H., Giardiello, F.M., Powe, N.R., Hylind, L., Robinson, A., Hutcheon, D.F., Kafonek, D.R., Brandenburg, S., Wu, Y., He, X., and Feinberg, A.P. (2004) Loss of imprinting of insulin growth factor II gene: a potential heritable biomarker for colon neoplasia predisposition. Gastroenterology 126, 964–970.PubMedCrossRefGoogle Scholar
  12. 12.
    Reik, W. (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432.PubMedCrossRefGoogle Scholar
  13. 13.
    Liou, J.M., Wu, M.S., Lin, J.T., Wang, H.P., Huang, S.P., Chiu, H.M., Lee, Y.C., Lin, Y.B., Shun, C.T., and Liang, J.T. (2007) Loss of imprinting of insulin-like growth factor II is associated with increased risk of proximal colon cancer. Eur J Cancer 43, 1276–1282.PubMedCrossRefGoogle Scholar
  14. 14.
    Sullivan, M.J., Taniguchi, T., Jhee, A., Kerr, N., and Reeve, A.E. (1999) Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation. Oncogene 18,7527–7534.PubMedCrossRefGoogle Scholar
  15. 15.
    Cui, H., Onyango, P., Brandenburg, S., Wu, Y., Hsieh, C.L., and Feinberg, A.P. (2002) Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res 62, 6442–6446.PubMedGoogle Scholar
  16. 16.
    Cui, H., Cruz-Correa, M., Giardiello, F.M., Hutcheon, D.F., Kafonek, D.R., Brandenburg, S., Wu, Y., He, X., Powe, N.R., and Feinberg, A.P. (2003) Loss of IGF2 Imprinting: A Potential Marker of Colorectal Cancer Risk. Science 299, 1753–1755.PubMedCrossRefGoogle Scholar
  17. 17.
    Woodson, K., Flood, A., Green, L., Tangrea, J.A., Hanson, J., Cash, B., Schatzkin, A., and Schoenfeld, P. (2004) Loss of Insulin-Like Growth Factor-II Imprinting and the Presence of Screen-Detected Colorectal Adenomas in Women. Journal of the National Cancer Institute 96, 407–410.PubMedCrossRefGoogle Scholar
  18. 18.
    Cheng, Y.W., Idrees, K., Shattock, R., Khan, S.A., Zeng, Z., Brennan, C.W., Paty, P., and Barany, F. (2010) Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer. Int J Cancer 127, 568–577.PubMedCrossRefGoogle Scholar
  19. 19.
    Kaaks, R., Stattin, P., Villar, S., Poetsch, A.R., Dossus, L., Nieters, A., Riboli, E., Palmqvist, R., Hallmans, G., Plass, C., and Friesen, M.D. (2009) Insulin-like Growth Factor-II Methylation Status in Lymphocyte DNA and Colon Cancer Risk in the Northern Sweden Health and Disease Cohort. Cancer Research 69, 5400–5405.PubMedCrossRefGoogle Scholar
  20. 20.
    Murrell, A., Ito, Y., Verde, G., Huddleston, J., Woodfine, K., Silengo, M.C., Spreafico, F., Perotti, D., De Crescenzo, A., Sparago, A., Cerrato, F., and Riccio, A. (2008) Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer. PLoS One 3, e1849.PubMedCrossRefGoogle Scholar
  21. 21.
    Ito, Y., Koessler, T., Ibrahim, A.E., Rai, S., Vowler, S.L., Abu-Amero, S., Silva, A.L., Maia, A.T., Huddleston, J.E., Uribe-Lewis, S., Woodfine, K., Jagodic, M., Nativio, R., Dunning, A., Moore, G., Klenova, E., Bingham, S., Pharoah, P.D., Brenton, J.D., Beck, S., Sandhu, M.S., and Murrell, A. (2008) Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer. Hum Mol Genet 17, 2633–2643.PubMedCrossRefGoogle Scholar
  22. 22.
    Belshaw, N.J., Pal, N., Tapp, H.S., Dainty, J.R., Lewis, M.P., Williams, M.R., Lund, E.K., and Johnson, I.T. (2010) Patterns of DNA methylation in individual colonic crypts reveal aging and cancer-related field defects in the morphologically normal mucosa. Carcinogenesis 31, 1158–1163.PubMedCrossRefGoogle Scholar
  23. 23.
    Heijmans, B.T., Kremer, D., Tobi, E.W., Boomsma, D.I., and Slagboom, P.E. (2007) Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Human Molecular Genetics 16, 547–554.PubMedCrossRefGoogle Scholar
  24. 24.
    Heijmans, B.T., Tobi, E.W., Stein, A.D., Putter, H., Blauw, G.J., Susser, E.S., Slagboom, P.E., and Lumey, L.H. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences 105, 17046–17049.CrossRefGoogle Scholar
  25. 25.
    Hunt, K.J., Toniolo, P., Akhmedkhanov, A., Lukanova, A., Dechaud, H., Rinaldi, S., Zeleniuch-Jacquotte, A., Shore, R.E., Riboli, E., and Kaaks, R. (2002) Insulin-like Growth Factor II and Colorectal Cancer Risk in Women. Cancer Epidemiology Biomarkers & Prevention 11, 901–905.Google Scholar
  26. 26.
    Cropley, J.E., Martin, D.I., and Suter, C.M. (2008) Germline epimutation in humans. Pharmacogenomics 9, 1861–1868.PubMedCrossRefGoogle Scholar
  27. 27.
    Niessen, R.C., R.M. Hofstra, Westers, H., Ligtenberg, M.J., Kooi, K., Jager, P.O., de Groote, M.L., Dijkhuizen, T., Olderode-Berends, M.J., Hollema, H., Kleibeuker, J.H., and Sijmons, R.H. (2009) Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer 48, 737–744.PubMedCrossRefGoogle Scholar
  28. 28.
    van Roon, E.H., van Puijenbroek, M., Middeldorp, A., van Eijk, R., de Meijer, E.J., Erasmus, D., Wouters, K.A., van Engeland, M., Oosting, J., Hes, F.J., Tops, C.M., van Wezel, T., Boer, J.M., and Morreau, H. (2010) Early onset MSI-H colon cancer with MLH1 promoter methylation, is there a genetic predisposition? BMC Cancer 10, 180.PubMedCrossRefGoogle Scholar
  29. 29.
    Goel, A., Nguyen, T.P., Leung, H.C., Nagasaka, T., Rhees, J., Hotchkiss, E., Arnold, M., Banerji, P., Koi, M., Kwok, C.T., Packham, D., Lipton, L., Boland, C.R., Ward, R.L., and Hitchins, M.P. (2010) De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int J Cancer Google Scholar
  30. 30.
    Gazzoli, I., Loda, M., Garber, J., Syngal, S., and Kolodner, R.D. (2002) A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res 62, 3925–3928.PubMedGoogle Scholar
  31. 31.
    Valle, L., Carbonell, P., Fernandez, V., Dotor, A.M., Sanz, M., Benitez, J., and Urioste, M. (2007) MLH1 germline epimutations in selected patients with early-onset non-polyposis colorectal cancer. Clin Genet 71, 232–237.PubMedCrossRefGoogle Scholar
  32. 32.
    Hitchins, M.P., Wong, J.J., Suthers, G., Suter, C.M., Martin, D.I., Hawkins, N.J., and Ward, R.L. (2007) Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 356, 697–705.PubMedCrossRefGoogle Scholar
  33. 33.
    Chan, T.L., Yuen, S.T., Kong, C.K., Chan, Y.W., Chan, A.S., Ng, W.F., Tsui, W.Y., Lo, M.W., Tam, W.Y., Li, V.S., and Leung, S.Y. (2006) Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 38, 1178–1183.PubMedCrossRefGoogle Scholar
  34. 34.
    Horsthemke, B. (2007) Heritable germline epimutations in humans. Nat Genet 39, 573–574; author reply 575–576.Google Scholar
  35. 35.
    Chong, S., Youngson, N.A., and Whitelaw, E. (2007) Heritable germline epimutation is not the same as transgenerational epigenetic inheritance. Nat Genet 39, 574–575.PubMedCrossRefGoogle Scholar
  36. 36.
    Suter, C.M. and Martin, D.I. (2007) Inherited epimutation or a haplotypic basis for the propensity to silence? Nat Genet 39, 573; author reply 576.Google Scholar
  37. 37.
    Ligtenberg, M.J., Kuiper, R.P., Chan, T.L., Goossens, M., Hebeda, K.M., Voorendt, M., Lee, T.Y., Bodmer, D., Hoenselaar, E., Hendriks-Cornelissen, S.J., Tsui, W.Y., Kong, C.K., Brunner, H.G., van Kessel, A.G., Yuen, S.T., van Krieken, J.H., Leung, S.Y., and Hoogerbrugge, N. (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 41, 112–117.PubMedCrossRefGoogle Scholar
  38. 38.
    Venkatachalam, R., Ligtenberg, M.J., Hoogerbrugge, N., Schackert, H.K., Gorgens, H., Hahn, M.M., Kamping, E.J., Vreede, L., Hoenselaar, E., van der Looij, E., Goossens, M., Churchman, M., Carvajal-Carmona, L., Tomlinson, I.P., de Bruijn, D.R., Van Kessel, A.G., and Kuiper, R.P. (2010) Germline Epigenetic Silencing of the Tumor Suppressor Gene PTPRJ in Early-Onset Familial Colorectal Cancer. Gastroenterology Google Scholar
  39. 39.
    Deng, G., Chen, A., Hong, J., Chae, H.S., and Kim, Y.S. (1999) Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res 59, 2029–2033.PubMedGoogle Scholar
  40. 40.
    Poynter, J.N., Siegmund, K.D., Weisenberger, D.J., Long, T.I., Thibodeau, S.N., Lindor, N., Young, J., Jenkins, M.A., Hopper, J.L., Baron, J.A., Buchanan, D., Casey, G., Levine, A.J., Le Marchand, L., Gallinger, S., Bapat, B., Potter, J.D., Newcomb, P.A., Haile, R.W., and Laird, P.W. (2008) Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening. Cancer Epidemiol Biomarkers Prev 17, 3208–3215.PubMedCrossRefGoogle Scholar
  41. 41.
    Suter, C.M., Martin, D.I., and Ward, R.L. (2004) Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 36, 497–501.PubMedCrossRefGoogle Scholar
  42. 42.
    Miyakura, Y., Sugano, K., Akasu, T., Yoshida, T., Maekawa, M., Saitoh, S., Sasaki, H., Nomizu, T., Konishi, F., Fujita, S., Moriya, Y., and Nagai, H. (2004) Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset sporadic colon cancers with microsatellite instability. Clin Gastroenterol Hepatol 2, 147–156.PubMedCrossRefGoogle Scholar
  43. 43.
    Martin, D.I., Ward, R., and Suter, C.M. (2005) Germline epimutation: A basis for epigenetic disease in humans. Ann N Y Acad Sci 1054, 68–77.PubMedCrossRefGoogle Scholar
  44. 44.
    Hitchins, M., Williams, R., Cheong, K., Halani, N., Lin, V., Packham, D., Ku, S., Buckle, A., Hawkins, N., Burn, J., Gallinger, S., Goldblatt, J., Kirk, J., Tomlinson, I., Scott, R., Spigelman, A., Suter, C., Martin, D., Suthers, G., and Ward, R. (2005) MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 129, 1392–1399.PubMedCrossRefGoogle Scholar
  45. 45.
    Gylling, A., Ridanpaa, M., Vierimaa, O., Aittomaki, K., Avela, K., Kaariainen, H., Laivuori, H., Poyhonen, M., Sallinen, S.L., Wallgren-Pettersson, C., Jarvinen, H.J., Mecklin, J.P., and Peltomaki, P. (2009) Large genomic rearrangements and germline epimutations in Lynch syndrome. Int J Cancer 124, 2333–2340.PubMedCrossRefGoogle Scholar
  46. 46.
    Morak, M., Schackert, H.K., Rahner, N., Betz, B., Ebert, M., Walldorf, C., Royer-Pokora, B., Schulmann, K., von Knebel-Doeberitz, M., Dietmaier, W., Keller, G., Kerker, B., Leitner, G., and Holinski-Feder, E. (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, 804–811.PubMedCrossRefGoogle Scholar
  47. 47.
    Teixeira, F.K., Heredia, F., Sarazin, A., Roudier, F., Boccara, M., Ciaudo, C., Cruaud, C., Poulain, J., Berdasco, M., Fraga, M.F., Voinnet, O., Wincker, P., Esteller, M., and Colot, V. (2009) A role for RNAi in the selective correction of DNA methylation defects. Science 323, 1600–1604.PubMedCrossRefGoogle Scholar
  48. 48.
    Dobrovic, A. and Kristensen, L.S. (2009) DNA methylation, epimutations and cancer predisposition. Int J Biochem Cell Biol 41, 34–39.PubMedCrossRefGoogle Scholar
  49. 49.
    Li, Y., Zhu, J., Tian, G., Li, N., Li, Q., Ye, M., Zheng, H., Yu, J., Wu, H., Sun, J., Zhang, H., Chen, Q., Luo, R., Chen, M., He, Y., Jin, X., Zhang, Q., Yu, C., Zhou, G., Sun, J., Huang, Y., Zheng, H., Cao, H., Zhou, X., Guo, S. et al., (2010) The DNA methylome of human peripheral blood mononuclear cells. PLoS Biol 8, e1000533.PubMedCrossRefGoogle Scholar
  50. 50.
    Alvarez, S., Diaz-Uriarte, R., Osorio, A., Barroso, A., Melchor, L., Paz, M.F., Honrado, E., Rodriguez, R., Urioste, M., Valle, L., Diez, O., Cigudosa, J.C., Dopazo, J., Esteller, M., and Benitez, J. (2005) A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation. Clin Cancer Res 11, 1146–1153.PubMedGoogle Scholar
  51. 51.
    Iwamoto, T., Yamamoto, N., Taguchi, T., Tamaki, Y., and Noguchi, S. (2010) BRCA1 promoter methylation in peripheral blood cells is associated with increased risk of breast cancer with BRCA1 promoter methylation. Breast Cancer Research and Treatment 1–9.Google Scholar
  52. 52.
    Chen, Y., Toland, A., McLennan, J., Fridlyand, J., Crawford, B., Costello, J., and Ziegler, J. (2006) Lack of germ-line promoter methylation in BRCA1-negative families with familial breast cancer. Genet Test 10, 281–284.PubMedCrossRefGoogle Scholar
  53. 53.
    Snell, C., Krypuy, M., Wong, E.M., Loughrey, M.B., and Dobrovic, A. (2008) BRCA1 promoter methylation in peripheral blood DNA of mutation negative familial breast cancer patients with a BRCA1 tumour phenotype. Breast Cancer Res 10, R12.PubMedCrossRefGoogle Scholar
  54. 54.
    Wong, E.M., Southey, M.C., Fox, S.B., Brown, M.A., Dowty, J.G., Jenkins, M.A., Giles, G.G., Hopper, J., and Dobrovic, A. (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, 23–33.CrossRefGoogle Scholar
  55. 55.
    Kontorovich, T., Cohen, Y., Nir, U., and Friedman, E. (2009) Promoter methylation patterns of ATM, ATR, BRCA1, BRCA2 and p53 as putative cancer risk modifiers in Jewish BRCA1/BRCA2 mutation carriers. Breast Cancer Res Treat 116, 195–200.PubMedCrossRefGoogle Scholar
  56. 56.
    Flanagan, J.M., Munoz-Alegre, M., Henderson, S., Tang, T., Sun, P., Johnson, N., Fletcher, O., dos Santos Silva, I., Peto, J., Boshoff, C., Narod, S., and Petronis, A. (2009) Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. Human Molecular Genetics 18, 1332–1342.PubMedCrossRefGoogle Scholar
  57. 57.
    Maunakea, A.K., Nagarajan, R.P., Bilenky, M., Ballinger, T.J., D’Souza, C., Fouse, S.D., Johnson, B.E., Hong, C., Nielsen, C., Zhao, Y., Turecki, G., Delaney, A., Varhol, R., Thiessen, N., Shchors, K., Heine, V.M., Rowitch, D.H., Xing, X., Fiore, C., Schillebeeckx, M., Jones, S.J., Haussler, D., Marra, M.A., Hirst, M., Wang, T. et al., (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466, 253–257.PubMedCrossRefGoogle Scholar
  58. 58.
    Flanagan, J.M. and Wild, L. (2007) An epigenetic role for noncoding RNAs and intragenic DNA methylation. Genome Biol 8, 307.PubMedCrossRefGoogle Scholar
  59. 59.
    Flanagan, J.M. (2010) Human Methylome Variation and the Rise of Epigenetic Epidemiology. Current Pharmacogenomics and Personalized Medicine 8, 89–91.CrossRefGoogle Scholar
  60. 60.
    Aran, D., Toperoff, G., Rosenberg, M., and Hellman, A. (2011) Replication timing-related and gene body-specific methylation of active human genes. Hum Mol Genet 20, 670–680.PubMedCrossRefGoogle Scholar
  61. 61.
    Appanah, R., Dickerson, D.R., Goyal, P., Groudine, M., and Lorincz, M.C. (2007) An unmethylated 3′ promoter-proximal region is required for efficient transcription initiation. PLoS Genet 3, e27.PubMedCrossRefGoogle Scholar
  62. 62.
    Wu, X., Rauch, T.A., Zhong, X., Bennett, W.P., Latif, F., Krex, D., and Pfeifer, G.P. (2010) CpG island hypermethylation in human astrocytomas. Cancer Res 70, 2718–2727.PubMedCrossRefGoogle Scholar
  63. 63.
    Zilberman, D., Gehring, M., Tran, R.K., Ballinger, T., and Henikoff, S. (2007) Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription. Nat Genet 39, 61–69.PubMedCrossRefGoogle Scholar
  64. 64.
    Wild, L. and Flanagan, J.M. (2010) Genome-wide hypomethylation in cancer may be a passive consequence of transformation. Biochim Biophys Acta 1806, 50–57.PubMedGoogle Scholar
  65. 65.
    Wild, L., Funes, J.M., Boshoff, C., and Flanagan, J.M. (2010) In vitro transformation of mesenchymal stem cells induces gradual genomic hypomethylation. Carcinogenesis 31, 1854–1862.PubMedCrossRefGoogle Scholar
  66. 66.
    Choi, J.Y., James, S.R., Link, P.A., McCann, S.E., Hong, C.C., Davis, W., Nesline, M.K., Ambrosone, C.B., and Karpf, A.R. (2009) Association between global DNA hypomethylation in leukocytes and risk of breast cancer. Carcinogenesis 30, 1889–1897.PubMedCrossRefGoogle Scholar
  67. 67.
    Lim, U., Flood, A., Choi, S.W., Albanes, D., Cross, A.J., Schatzkin, A., Sinha, R., Katki, H.A., Cash, B., Schoenfeld, P., and Stolzenberg-Solomon, R. (2008) Genomic methylation of leukocyte DNA in relation to colorectal adenoma among asymptomatic women. Gastroenterology 134, 47–55.PubMedCrossRefGoogle Scholar
  68. 68.
    Moore, L.E., Pfeiffer, R.M., Poscablo, C., Real, F.X., Kogevinas, M., Silverman, D., Garcia-Closas, R., Chanock, S., Tardon, A., Serra, C., Carrato, A., Dosemeci, M., Garcia-Closas, M., Esteller, M., Fraga, M., Rothman, N., and Malats, N. (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.PubMedCrossRefGoogle Scholar
  69. 69.
    Pufulete, M., Al-Ghnaniem, R., Leather, A.J., Appleby, P., Gout, S., Terry, C., Emery, P.W., and Sanders, T.A. (2003) Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124, 1240–1248.PubMedCrossRefGoogle Scholar
  70. 70.
    Ting Hsiung, D., Marsit, C.J., Houseman, E.A., Eddy, K., Furniss, C.S., McClean, M.D., and Kelsey, K.T. (2007) Global DNA Methylation Level in Whole Blood as a Biomarker in Head and Neck Squamous Cell Carcinoma. Cancer Epidemiology Biomarkers & Prevention 16, 108–114.CrossRefGoogle Scholar
  71. 71.
    Flanagan, J.M., Cocciardi, S., Waddell, N., Johnstone, C.N., Marsh, A., Henderson, S., Simpson, P., da Silva, L., Khanna, K., Lakhani, S., Boshoff, C., and Chenevix-Trench, G. (2010) DNA methylome of familial breast cancer identifies distinct profiles defined by mutation status. Am J Hum Genet. 86, 420–433.PubMedCrossRefGoogle Scholar
  72. 72.
    Wilhelm, C.S., Kelsey, K.T., Butler, R., Plaza, S., Gagne, L., Zens, M.S., Andrew, A.S., Morris, S., Nelson, H.H., Schned, A.R., Karagas, M.R., and Marsit, C.J. (2010) Implications of LINE1 methylation for bladder cancer risk in women. Clin Cancer Res 16, 1682–1689.PubMedCrossRefGoogle Scholar
  73. 73.
    Teschendorff, A.E., Menon, U., Gentry-Maharaj, A., Ramus, S.J., Gayther, S.A., Apostolidou, S., Jones, A., Lechner, M., Beck, S., Jacobs, I.J., and Widschwendter, M. (2009) An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One 4, e8274.PubMedCrossRefGoogle Scholar
  74. 74.
    Christensen, B.C., Houseman, E.A., Marsit, C.J., Zheng, S., Wrensch, M.R., Wiemels, J.L., Nelson, H.H., Karagas, M.R., Padbury, J.F., Bueno, R., Sugarbaker, D.J., Yeh, R.F., Wiencke, J.K., and Kelsey, K.T. (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5, e1000602.PubMedCrossRefGoogle Scholar
  75. 75.
    Rakyan, V.K., Down, T.A., Maslau, S., Andrew, T., Yang, T.P., Beyan, H., Whittaker, P., McCann, O.T., Finer, S., Valdes, A.M., Leslie, R.D., Deloukas, P., and Spector, T.D. (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20, 434–439.PubMedCrossRefGoogle Scholar
  76. 76.
    Foley, D.L., Craig, J.M., Morley, R., Olsson, C.A., Dwyer, T., Smith, K., and Saffery, R. (2009). Prospects for epigenetic epidemiology. Am J Epidemiol 169, 389–400.PubMedCrossRefGoogle Scholar
  77. 77.
    Teschendorff, A.E., Menon, U., Gentry-Maharaj, A., Ramus, S.J., Weisenberger, D.J., Shen, H., Campan, M., Noushmehr, H., Bell, C.G., Maxwell, A.P., Savage, D.A., Mueller-Holzner, E., Marth, C., Kocjan, G., Gayther, S.A., Jones, A., Beck, S., Wagner, W., Laird, P.W., Jacobs, I.J., and Widschwendter, M. (2010) Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res 20, 440–446.PubMedCrossRefGoogle Scholar
  78. 78.
    Schneider, E., Pliushch, G., El Hajj, N., Galetzka, D., Puhl, A., Schorsch, M., Frauenknecht, K., Riepert, T., Tresch, A., Muller, A.M., Coerdt, W., Zechner, U., and Haaf, T. (2010) Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns. Nucleic Acids Res 38, 3880–3890.PubMedCrossRefGoogle Scholar
  79. 79.
    Fraga, M.F., Ballestar, E., Paz, M.F., Ropero, S., Setien, F., Ballestar, M.L., Heine-Suner, D., Cigudosa, J.C., Urioste, M., Benitez, J., Boix-Chornet, M., Sanchez-Aguilera, A., Ling, C., Carlsson, E., Poulsen, P., Vaag, A., Stephan, Z., Spector, T.D., Wu, Y.Z., Plass, C., and Esteller, M. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102, 10604–10609.PubMedCrossRefGoogle Scholar
  80. 80.
    Gonzalo, S. (2010) Epigenetic alterations in aging. J Appl Physiol 109, 586–597.PubMedCrossRefGoogle Scholar
  81. 81.
    Chen, R.Z., Pettersson, U., Beard, C., Jackson-Grusby, L., and Jaenisch, R. (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395, 89–93.PubMedCrossRefGoogle Scholar
  82. 82.
    Calvanese, V., Lara, E., Kahn, A., and Fraga, M.F. (2009) The role of epigenetics in aging and age-related diseases. Ageing Res Rev 8, 268–276.PubMedCrossRefGoogle Scholar
  83. 83.
    Eckhardt, F., Lewin, J., Cortese, R., Rakyan, V.K., Attwood, J., Burger, M., Burton, J., Cox, T.V., Davies, R., Down, T.A., Haefliger, C., Horton, R., Howe, K., Jackson, D.K., Kunde, J., Koenig, C., Liddle, J., Niblett, D., Otto, T., Pettett, R., Seemann, S., Thompson, C., West, T., Rogers, J., Olek, A. et al., (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38, 1378–1385.PubMedCrossRefGoogle Scholar
  84. 84.
    Kaminsky, Z.A., Tang, T., Wang, S.C., Ptak, C., Oh, G.H., Wong, A.H., Feldcamp, L.A., Virtanen, C., Halfvarson, J., Tysk, C., McRae, A.F., Visscher, P.M., Montgomery, G.W., Gottesman, II, Martin, N.G., and Petronis, A. (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41, 240–245.PubMedCrossRefGoogle Scholar
  85. 85.
    Rakyan, V.K., Down, T.A., Thorne, N.P., Flicek, P., Kulesha, E., Graf, S., Tomazou, E.M., Backdahl, L., Johnson, N., Herberth, M., Howe, K.L., Jackson, D.K., Miretti, M.M., Fiegler, H., Marioni, J.C., Birney, E., Hubbard, T.J., Carter, N.P., Tavare, S., and Beck, S. (2008) An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs). Genome Res 18, 1518–1529.PubMedCrossRefGoogle Scholar
  86. 86.
    Straussman, R., Nejman, D., Roberts, D., Steinfeld, I., Blum, B., Benvenisty, N., Simon, I., Yakhini, Z., and Cedar, H. (2009) Developmental programming of CpG island methylation profiles in the human genome. Nat Struct Mol Biol 16, 564–571.PubMedCrossRefGoogle Scholar
  87. 87.
    Illingworth, R., Kerr, A., Desousa, D., Jorgensen, H., Ellis, P., Stalker, J., Jackson, D., Clee, C., Plumb, R., Rogers, J., Humphray, S., Cox, T., Langford, C., and Bird, A. (2008) A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol 6, e22.PubMedCrossRefGoogle Scholar
  88. 88.
    Feinberg, A.P. (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440.PubMedCrossRefGoogle Scholar
  89. 89.
    Tobi, E.W., Lumey, L.H., Talens, R.P., Kremer, D., Putter, H., Stein, A.D., Slagboom, P.E., and Heijmans, B.T. (2009) DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 18, 4046–4053.PubMedCrossRefGoogle Scholar
  90. 90.
    Steegers-Theunissen, R.P., Obermann-Borst, S.A., Kremer, D., Lindemans, J., Siebel, C., Steegers, E.A., Slagboom, P.E., and Heijmans, B.T. (2009) Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One 4, e7845.PubMedCrossRefGoogle Scholar
  91. 91.
    Xu, X.F. and Du, L.Z. (2010) Epigenetics in neonatal diseases. Chin Med J (Engl) 123, 2948–2954.Google Scholar
  92. 92.
    Hilakivi-Clarke, L. and de Assis, S. (2006) Fetal origins of breast cancer. Trends Endocrinol Metab 17, 340–348.PubMedCrossRefGoogle Scholar
  93. 93.
    Burdge, G.C., Lillycrop, K.A., and Jackson, A.A. (2009) Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale? Br J Nutr 101, 619–630.PubMedCrossRefGoogle Scholar
  94. 94.
    Waterland, R.A., Lin, J.R., Smith, C.A., and Jirtle, R.L. (2006). Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 15, 705–716.PubMedCrossRefGoogle Scholar
  95. 95.
    Dolinoy, D.C., Weidman, J.R., Waterland, R.A., and Jirtle, R.L. (2006) Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect 114, 567–572.PubMedCrossRefGoogle Scholar
  96. 96.
    Schwartz, Y.B., Kahn, T.G., Stenberg, P., Ohno, K., Bourgon, R., and Pirrotta, V. (2010) Alternative epigenetic chromatin states of polycomb target genes. PLoS Genet 6, e1000805.PubMedCrossRefGoogle Scholar
  97. 97.
    Christensen, B.C., Kelsey, K.T., Zheng, S., Houseman, E.A., Marsit, C.J., Wrensch, M.R., Wiemels, J.L., Nelson, H.H., Karagas, M.R., Kushi, L.H., Kwan, M.L., and Wiencke, J.K. (2010) Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake. PLoS Genet 6, e1001043.PubMedCrossRefGoogle Scholar
  98. 98.
    Gluckman, P.D. and Hanson, M.A. (2004) Living with the past: evolution, development, and patterns of disease. Science. 305, 1733–1736.PubMedCrossRefGoogle Scholar
  99. 99.
    Li, S., Hursting, S.D., Davis, B.J., McLachlan, J.A., and Barrett, J.C. (2003) Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann N Y Acad Sci 983, 161–169.PubMedCrossRefGoogle Scholar
  100. 100.
    Newbold, R.R. (2008) Prenatal exposure to diethylstilbestrol (DES). Fertil Steril 89, e55–56.PubMedCrossRefGoogle Scholar
  101. 101.
    Sato, K., Fukata, H., Kogo, Y., Ohgane, J., Shiota, K., and Mori, C. (2006) Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice. Endocr J 53, 331–337.PubMedCrossRefGoogle Scholar
  102. 102.
    Lagiou, P. (2007) Intrauterine factors and breast cancer risk. Lancet Oncol 8, 1047–1048.PubMedCrossRefGoogle Scholar
  103. 103.
    Yu, W., Gius, D., Onyango, P., Muldoon-Jacobs, K., Karp, J., Feinberg, A.P., and Cui, H. (2008) Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451, 202–206.PubMedCrossRefGoogle Scholar
  104. 104.
    Tufarelli, C., Stanley, J.A., Garrick, D., Sharpe, J.A., Ayyub, H., Wood, W.G., and Higgs, D.R. (2003) Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet 34, 157–165.PubMedCrossRefGoogle Scholar
  105. 105.
    Katayama, S., Tomaru, Y., Kasukawa, T., Waki, K., Nakanishi, M., Nakamura, M., Nishida, H., Yap, C.C., Suzuki, M., Kawai, J., Suzuki, H., Carninci, P., Hayashizaki, Y., Wells, C., Frith, M., Ravasi, T., Pang, K.C., Hallinan, J., Mattick, J., Hume, D.A., Lipovich, L., Batalov, S., Engstrom, P.G., Mizuno, Y., Faghihi, M.A. et al., (2005) Antisense transcription in the mammalian transcriptome. Science 309, 1564–1566.PubMedCrossRefGoogle Scholar
  106. 106.
    Peters, J. and Williamson, C.M. (2007) Control of imprinting at the Gnas cluster. Epigenetics 2, 207–213.PubMedCrossRefGoogle Scholar
  107. 107.
    Shlien, A. and Malkin, D. (2009) Copy number variations and cancer. Genome Med 1, 62.PubMedCrossRefGoogle Scholar
  108. 108.
    Feinberg, A.P. and Tycko, B. (2004) The history of cancer epigenetics. Nat Rev Cancer 4, 143–153.PubMedCrossRefGoogle Scholar
  109. 109.
    Ordway, J.M., Budiman, M.A., Korshunova, Y., Maloney, R.K., Bedell, J.A., Citek, R.W., Bacher, B., Peterson, S., Rohlfing, T., Hall, J., Brown, R., Lakey, N., Doerge, R.W., Martienssen, R.A., Leon, J., McPherson, J.D., and Jeddeloh, J.A. (2007) Identification of novel high-frequency DNA methylation changes in breast cancer. PLoS One 2, e1314.PubMedCrossRefGoogle Scholar
  110. 110.
    Wacholder, S., Hartge, P., Prentice, R., Garcia-Closas, M., Feigelson, H.S., Diver, W.R., Thun, M.J., Cox, D.G., Hankinson, S.E., Kraft, P., Rosner, B., Berg, C.D., Brinton, L.A., Lissowska, J., Sherman, M.E., Chlebowski, R., Kooperberg, C., Jackson, R.D., Buckman, D.W., Hui, P., Pfeiffer, R., Jacobs, K.B., Thomas, G.D., Hoover, R.N., Gail, M.H. et al., (2010) Performance of common genetic variants in breast-cancer risk models. N Engl J Med 362, 986–993.PubMedCrossRefGoogle Scholar
  111. 111.
    Beck, S. (2010) Taking the measure of the methylome. Nat Biotechnol 28, 1026–1028.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Surgery and CancerImperial CollegeLondonUK

Personalised recommendations