Skip to main content
SpringerLink
Log in

Early Epigenetic Markers for Precision Medicine

  • Protocol
  • First Online:
Cancer Epigenetics for Precision Medicine

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1856))

Abstract

Over the last years, epigenetic changes, including DNA methylation and histone modifications detected in early tumorigenesis and cancer progression, have been proposed as biomarkers for cancer detection, tumor prognosis, and prediction to treatment response. Importantly for the clinical use of DNA methylation biomarkers, specific methylation signatures can be detected in many body fluids including serum/plasma samples. Several of these potential epigenetic biomarkers detected in women’s cancers, colorectal cancers, prostate, pancreatic, gastric, and lung cancers are discussed. Studies conducted in breast cancer, for example, found that aberrant methylation detection of several genes in serum DNA and genome-wide epigenetic change could be used for early breast cancer diagnosis and prediction of breast cancer risk. In colorectal cancers, numerous studies have been conducted to identify specific methylation markers important for CRC detection and in fact clinical assays evaluating the methylation status of SEPT19 gene and vimentin, became commercially available. Furthermore, some epigenetic changes detected in gastric washes have been suggested as potential circulating noninvasive biomarkers for the early detection of gastric cancers. For the early detection of prostate cancer, few epigenetic markers have shown a better sensitivity and specificity than serum PSA, indicating that the inclusion of these markers together with current screening tools, could improve early diagnosis and may reduce unnecessary repeat biopsies. Similarly, in pancreatic cancers, abnormal DNA methylation of several genes including NPTX2, have been suggested as a diagnostic biomarker. Epigenetic dysregulation was also observed in several tumor suppressor genes and miRNAs in lung cancer patients, suggesting the important role of these changes in cancer initiation and progression. In conclusion, epigenetic changes detected in biological fluids could play an essential role in the early detection of several cancer types and this may have a great impact for the cancer precision medicine field.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
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

Similar content being viewed by others

References

  1. Rodriguez-Paredes M, Esteller M (2011) Cancer epigenetics reaches mainstream oncology. Nat Med 17(3):330–339

    Google Scholar 

  2. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692

    Google Scholar 

  3. Wittenberger T, Sleigh S, Reisel D, Zikan M, Wahl B, Alunni-Fabbroni M, Jones A, Evans I, Koch J, Paprotka T, Lempiainen H, Rujan T, Rack B, Cibula D, Widschwendter M (2014) DNA methylation markers for early detection of women's cancer: promise and challenges. Epigenomics 6(3):311–327

    Google Scholar 

  4. Dietrich D (2018) DNA methylation analysis from body fluids. Methods Mol Biol 1655:239–249

    Google Scholar 

  5. Gormally E, Caboux E, Vineis P, Hainaut P (2007) Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. Mutat Res 635(2–3):105–117

    Google Scholar 

  6. Jones A, Lechner M, Fourkala EO, Kristeleit R, Widschwendter M (2010) Emerging promise of epigenetics and DNA methylation for the diagnosis and management of women's cancers. Epigenomics 2(1):9–38

    Google Scholar 

  7. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 11(10):726–734

    Google Scholar 

  8. Locke WJ, Clark SJ (2012) Epigenome remodeling in breast cancer: insights from an early in vitro model of carcinogenesis. Breast Cancer Res 14(6):215

    Google Scholar 

  9. Hinshelwood RA, Huschtscha LI, Melki J, Stirzaker C, Abdipranoto A, Vissel B, Ravasi T, Wells CA, Hume DA, Reddel RR, Clark SJ (2007) Concordant epigenetic silencing of transforming growth factor-beta signaling pathway genes occurs early in breast carcinogenesis. Cancer Res 67(24):11517–11527

    Google Scholar 

  10. Locke WJ, Zotenko E, Stirzaker C, Robinson MD, Hinshelwood RA, Stone A, Reddel RR, Huschtscha LI, Clark SJ (2015) Coordinated epigenetic remodelling of transcriptional networks occurs during early breast carcinogenesis. Clin Epigenetics 7(1):52

    Google Scholar 

  11. Severi G, Southey MC, English DR, Jung CH, Lonie A, McLean C, Tsimiklis H, Hopper JL, Giles GG, Baglietto L (2014) Epigenome-wide methylation in DNA from peripheral blood as a marker of risk for breast cancer. Breast Cancer Res Treat 148(3):665–673

    Google Scholar 

  12. Tang Q, Cheng J, Cao X, Surowy H, Burwinkel B (2016) Blood-based DNA methylation as biomarker for breast cancer: a systematic review. Clin Epigenetics 8:115

    Google Scholar 

  13. Uehiro N, Sato F, Pu F, Tanaka S, Kawashima M, Kawaguchi K, Sugimoto M, Saji S, Toi M (2016) Circulating cell-free DNA-based epigenetic assay can detect early breast cancer. Breast Cancer Res 18(1):129

    Google Scholar 

  14. van Veldhoven K, Polidoro S, Baglietto L, Severi G, Sacerdote C, Panico S, Mattiello A, Palli D, Masala G, Krogh V (2015) Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis. Clin Epigenetics 7:67

    Google Scholar 

  15. Ibanez de Caceres I, Battagli C, Esteller M, Herman JG, Dulaimi E, Edelson MI, Bergman C, Ehya H, Eisenberg BL, Cairns P (2004) Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res 64(18):6476–6481

    Google Scholar 

  16. Fiegl H, Gattringer C, Widschwendter A, Schneitter A, Ramoni A, Sarlay D, Gaugg I, Goebel G, Müller HM, Mueller-Holzner E, Marth C, Widschwendter M (2004) Methylated DNA collected by tampons--a new tool to detect endometrial cancer. Cancer Epidemiol Biomark Prev 13(5):882–888

    Google Scholar 

  17. Wentzensen N, Bakkum-Gamez JN, Killian JK, Sampson J, Guido R, Glass A, Adams L, Luhn P, Brinton LA, Rush B, d'Ambrosio L, Gunja M, Yang HP, Garcia-Closas M, Lacey JV Jr, Lissowska J, Podratz K, Meltzer P, Shridhar V, Sherman M (2014) Discovery and validation of methylation markers for endometrial cancer. Int J Cancer 135(8):1860–1868

    Google Scholar 

  18. Bakkum-Gamez JN, Wentzensen N, Maurer MJ, Hawthorne KM, Voss JS, Kroneman TN, Famuyide AO, Clayton AC, Halling KC, Kerr SE, Cliby WA, Dowdy SC, Kipp BR, Mariani A, Oberg AL, Podratz KC, Shridhar V, Sherman ME (2015) Detection of endometrial cancer via molecular analysis of DNA collected with vaginal tampons. Gynecol Oncol 137(1):14–22

    Google Scholar 

  19. Wisman GB, Nijhuis ER, Hoque MO, Reesink-Peters N, Koning AJ, Volders HH, Buikema HJ, Boezen HM, Hollema H, Schuuring E, Sidransky D, van der Zee AG (2006) Assessment of gene promoter hypermethylation for detection of cervical neoplasia. Int J Cancer 119(8):1908–1914

    Google Scholar 

  20. Lendvai A, Johannes F, Grimm C, Eijsink JJ, Wardenaar R, Volders HH, Klip HG, Hollema H, Jansen RC, Schuuring E, Wisman GB, van der Zee AG (2012) Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia. Epigenetics 7(11):1268–1278

    Google Scholar 

  21. Wilting SM, Miok V, Jaspers A, Boon D, Sorgard H, Lando M, Snoek BC, van Wieringen WN, Meijer CJ, Lyng H, Snijders PJ, Steenbergen RD (2016) Aberrant methylation-mediated silencing of microRNAs contributes to HPV-induced anchorage independence. Oncotarget 7(28):43805–43819

    Google Scholar 

  22. Lorincz AT (2016) Virtues and weaknesses of DNA methylation as a test for cervical cancer prevention. Acta Cytol 60(6):501–512

    Google Scholar 

  23. Binefa G, Rodríguez-Moranta F, Teule A, Medina-Hayas M (2014) Colorectal cancer: from prevention to personalized medicine. World J Gastroenterol 20(22):6786–6808

    Google Scholar 

  24. Nosho K, Irahara N, Shima K, Kure S, Kirkner GJ, Schernhammer ES, Hazra A, Hunter DJ, Quackenbush J, Spiegelman D, Giovannucci EL, Fuchs CS, Ogino S (2008) Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS One 3(11):e3698

    Google Scholar 

  25. Toiyama Y, Okugawa Y, Goel A (2014) DNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer. Biochem Biophys Res Commun 455(1–2):43–57

    Google Scholar 

  26. Hashimoto Y, Zumwalt TJ, Goel A (2016) DNA methylation patterns as noninvasive biomarkers and targets of epigenetic therapies in colorectal cancer. Epigenomics 8(5):685–703

    Google Scholar 

  27. Yi JM, Dhir M, Guzzetta AA, Iacobuzio-Donahue CA, Heo K, Yang KM, Suzuki H, Toyota M, Kim HM, Ahuja N (2012) DNA methylation biomarker candidates for early detection of colon cancer. Tumour Biol 33(2):363–372

    Google Scholar 

  28. Mahasneh A, Al-Shaheri F, Jamal E (2017) Molecular biomarkers for an early diagnosis, effective treatment and prognosis of colorectal cancer: current updates. Exp Mol Pathol 102(3):475–483

    Google Scholar 

  29. Galanopoulos M, Tsoukalas N, Papanikolaou IS, Tolia M, Gazouli M, Mantzaris GJ (2017) Abnormal DNA methylation as a cell-free circulating DNA biomarker for colorectal cancer detection: a review of literature. World J Gastrointest Oncol 9(4):142–152

    Google Scholar 

  30. Oh T, Kim N, Moon Y, Kim MS, Hoehn BD, Park CH, Kim TS, Kim NK, Chung HC, An S (2013) Genome-wide identification and validation of a novel methylation biomarker, SDC2, for blood-based detection of colorectal cancer. J Mol Diagn 15(4):498–507

    Google Scholar 

  31. Herbst A, Rahmig K, Stieber P, Philipp A, Jung A, Ofner A, Crispin A, Neumann J, Lamerz R, Kolligs FT (2011) Methylation of NEUROG1 in serum is a sensitive marker for the detection of early colorectal cancer. Am J Gastroenterol 106(6):1110–1118

    Google Scholar 

  32. Gyparaki MT, Basdra EK, Papavassiliou AG (2013) DNA methylation biomarkers as diagnostic and prognostic tools in colorectal cancer. J Mol Med (Berl) 91(11):1249–1256

    Google Scholar 

  33. Warren JD, Xiong W, Bunker AM, Vaughn CP, Furtado LV, Roberts WL, Fang JC, Samowitz WS, Heichman KA (2011) Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer. BMC Med 9:133

    Google Scholar 

  34. Toth K, Sipos F, Kalmar A, Patai AV, Wichmann B, Stoehr R, Golcher H, Schellerer V, Tulassay Z, Molnar B (2012) Detection of methylated SEPT9 in plasma is a reliable screening method for both left- and right-sided colon cancers. PLoS One 7(9):e46000

    Google Scholar 

  35. Ned RM, Melillo S, Marrone M (2011) Fecal DNA testing for colorectal cancer screening: the coloSure™ test. PLoS Curr 3:RRN1220

    Google Scholar 

  36. Lind GE, Danielsen SA, Ahlquist T, Merok MA, Andresen K, Skotheim RI, Hektoen M, Rognum TO, Meling GI, Hoff G, Bretthauer M, Thiis-Evensen E, Nesbakken A, Lothe RA (2011) Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas. Mol Cancer 10:85

    Google Scholar 

  37. Ahlquist DA, Taylor WR, Mahoney DW, Zou H, Domanico M, Thibodeau SN, Boardman LA, Berger BM, Lidgard GP (2012) The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia. Clin Gastroenterol Hepatol 10(3):272–7.e1

    Google Scholar 

  38. American Cancer Society (2015) Global facts and figures. 3rd edn. pp. 28–32. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-3rd-edition.pdf. Accessed 21 Sep 2017

  39. Liu L, Cao L, Gong B, Yu J (2015) Novel biomarkers for the identification and targeted therapy of gastric cancer. Expert Rev Gastroenterol Hepatol 9(9):1217–1226

    Google Scholar 

  40. Nakamura J, Tanaka T, Kitajima Y, Noshiro H, Miyazaki K (2014) Methylation-mediated gene silencing as biomarkers of gastric cancer: a review. World J Gastroenterol 20(34):11991–12006

    Google Scholar 

  41. Lee TL, Leung WK, Chan MW, Ng EK, Tong JH, Lo KW, Chung SC, Sung JJ, To KF (2002) Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma. Clin Cancer Res 8(6):1761–1766

    Google Scholar 

  42. Leung WK, To KF, Chu ES, Chan MW, Bai AH, Ng EK, Chan FK, Sung JJ (2005) Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer. Br J Cancer 92(12):2190–2194

    Google Scholar 

  43. Watanabe Y, Kim HS, Castoro RJ, Chung W, Estecio MR, Kondo K, Guo Y, Ahmed SS, Toyota M, Itoh F, Suk KT, Cho MY, Shen L, Jelinek J, Issa JP (2009) Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes. Gastroenterology 136(7):2149–2158

    Google Scholar 

  44. Oishi Y, Watanabe Y, Yoshida Y, Sato Y, Hiraishi T, Oikawa R, Maehata T, Suzuki H, Toyota M, Niwa H, Suzuki M, Itoh F (2012) Hypermethylation of Sox17 gene is useful as a molecular diagnostic application in early gastric cancer. Tumour Biol 33(2):383–393

    Google Scholar 

  45. American Cancer Society (2017) Global facts and figures. 3rd edn. p. 10. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Accessed 21 Sep 2017

  46. Brait M, Banerjee M, Maldonado L, Ooki A, Loyo M, Guida E, Izumchenko E, Mangold L, Humphreys E, Rosenbaum E, Partin A, Sidransky D, Hoque MO (2017) Promoter methylation of MCAM, ERα and ERβ in serum of early stage prostate cancer patients. Oncotarget 8(9):15431–15440

    Google Scholar 

  47. Wu T, Giovannucci E, Welge J, Mallick P, Tang WY, Ho SM (2011) Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a meta-analysis. Br J Cancer 105(1):65–73

    Google Scholar 

  48. Stewart GD, Van Neste L, Delvenne P, Delrée P, Delga A, McNeill SA, O'Donnell M, Clark J, Van Criekinge W, Bigley J, Harrison DJ (2013) Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. J Urol 189(3):1110–1116

    Google Scholar 

  49. Levenson VV, Melnikov AA (2011) The MethDet: a technology for biomarker development. Expert Rev Mol Diagn 11(8):807–812

    Google Scholar 

  50. Sato N, Fukushima N, Maitra A, Matsubayashi H, Yeo CJ, Cameron JL, Hruban RH, Goggins M (2003) Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res 63(13):3735–3742

    Google Scholar 

  51. Park JK, Ryu JK, Yoon WJ, Lee SH, Lee GY, Jeong KS, Kim YT, Yoon YB (2012) The role of quantitative NPTX2 hypermethylation as a novel serum diagnostic marker in pancreatic cancer. Pancreas 41(1):95–101

    Google Scholar 

  52. Shimizu H, Horii A, Sunamura M, Motoi F, Egawa S, Unno M, Fukushige S (2011) Identification of epigenetically silenced genes in human pancreatic cancer by a novel method "microarray coupled with methyl-CpG targeted transcriptional activation" (MeTA-array). Biochem Biophys Res Commun 411(1):162–167

    Google Scholar 

  53. Nones K, Waddell N, Song S, Patch AM, Miller D, Johns A, Wu J, Kassahn KS, Wood D, Bailey P, Fink L, Manning S, Christ AN, Nourse C, Kazakoff S, Taylor D, Leonard C, Chang DK, Jones MD, Thomas M, Watson C, Pinese M, Cowley M, Rooman I, Pajic M, Butturini G, Malpaga A, Corbo V, Crippa S, Falconi M, Zamboni G, Castelli P, Lawlor RT, Gill AJ, Scarpa A, Pearson JV, Biankin AV, Grimmond SM, APGI (2014) Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. Int J Cancer 135(5):1110–1118

    Google Scholar 

  54. Liggett T, Melnikov A, Yi QL, Replogle C, Brand R, Kaul K, Talamonti M, Abrams RA, Levenson V (2010) Differential methylation of cell-free circulating DNA among patients with pancreatic cancer versus chronic pancreatitis. Cancer 116(7):1674–1680

    Google Scholar 

  55. American Cancer Society (2017) Cancer facts and figures 2017. p. 18. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Accessed 21 Sep 2017

  56. Schwarzenbach H, Hoon DS, Pantel K (2011) Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 11(6):426–437

    Google Scholar 

  57. Tomasetti M, Amati M, Neuzil J, Santarelli L (2017) Circulating epigenetic biomarkers in lung malignancies: from early diagnosis to therapy. Lung Cancer 107:65–72

    Google Scholar 

  58. Vosa U, Vooder T, Kolde R, Vilo J, Metspalu A, Annilo T (2013) Meta-analysis of microRNA expression in lung cancer. Int J Cancer 132(12):2884–2893

    Google Scholar 

  59. Gao W, Xu J, Liu L, Shen H, Zeng H, Shu Y (2012) A systematic-analysis of predicted miR-21 targets identifies a signature for lung cancer. Biomed Pharmacother 66(1):21–28

    Google Scholar 

  60. Gao W, Shen H, Liu L, Xu J, Xu J, Shu Y (2011) MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis. J Cancer Res Clin Oncol 137(4):557–566

    Google Scholar 

  61. Zhu W, Liu X, He J, Chen D, Hunag Y, Zhang YK (2011) Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study. BMC Cancer 11:393

    Google Scholar 

  62. Donnem T, Fenton CG, Lonvik K, Berg T, Eklo K, Andersen S, Stenvold H, Al-Shibli K, Al-Saad S, Bremnes RM, Busund LT (2012) MicroRNA signatures in tumor tissue related to angiogenesis in non-small cell lung cancer. PLoS One 7(1):e29671

    Google Scholar 

  63. Joshi P, Middleton J, Jeon YJ, Garofalo M (2014) MicroRNAs in lung cancer. World J Methodol 4(2):59–72

    Google Scholar 

  64. Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabro E, Croce CM, Pastorino U, Sozzi G (2011) MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A 108(9):3713–3718

    Google Scholar 

  65. Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, Roz L, Conte D, Grassi M, Sverzellati N, Marchiano A, Negri E, La Vecchia C, Pastorino U (2014) Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. J Clin Oncol 32(8):768–773

    Google Scholar 

  66. Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M, Sültmann H, Lyko F (2007) The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res 67(4):1419–1423

    Google Scholar 

  67. Brzezianska E, Dutkowska A, Antczak A (2013) The significance of epigenetic alterations in lung carcinogenesis. Mol Biol Rep 40(1):309–325

    Google Scholar 

  68. Weiss G, Schlegel A, Kottwitz D, König T, Tetzner R (2017) Validation of the SHOX2/PTGER4 DNA methylation marker panel for plasma-based discrimination between patients with malignant and nonmalignant lung disease. J Thorac Oncol 12(1):77–84

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Kelly Government Solutions, Bethesda, MD, USA

    Ramona G. Dumitrescu

Authors
  1. Ramona G. Dumitrescu
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Kelly Government Solutions, Bethesda, MD, USA

    Ramona G. Dumitrescu

  2. Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Mukesh Verma

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Dumitrescu, R.G. (2018). Early Epigenetic Markers for Precision Medicine. In: Dumitrescu, R., Verma, M. (eds) Cancer Epigenetics for Precision Medicine . Methods in Molecular Biology, vol 1856. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8751-1_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-8751-1_1

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8750-4

  • Online ISBN: 978-1-4939-8751-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation