Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Genomic hypomethylation and CpG island hypermethylation in prostatic intraepithelial neoplasm

Abstract

Altered DNA methylation in cancer cells is characterized by focal CpG island hypermethylation and diffuse genomic hypomethylation. Both types of aberrant methylation are frequently found in human prostate adenocarcinoma (PCa). Prostatic intraepithelial neoplasm (PIN), a precursor lesion of PCa, has been demonstrated to contain CpG island hypermethylation, but little is known about the role of DNA hypomethylation. We analyzed the methylation status at 12 CpG island loci and at two repetitive DNA elements (LINE-1 and SAT2) from normal prostate (n = 20), PIN (n = 25), and PCa (n = 35) tissues using MethyLight assay or combined bisulfite restriction analysis. The methylation levels in LINE-1 and SAT2 decreased with progression of lesion types from normal prostate to PIN to PCa (P < 0.05), whereas promoter CpG island loci displayed increased methylation. Ten genes were found to be hypermethylated in a cancer-specific manner and were further analyzed in another set of PCa tissues (n = 64). The number of methylated genes was closely associated with TNM stage, Gleason sum, and preoperative serum PSA levels (P = 0.020, 0.073, 0.033, respectively). These results suggest that genomic hypomethylation and CpG island hypermethylation, common among PCas, are early events in prostate carcinogenesis and may be implicated in the development of PIN.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Bariol C, Suter C, Cheong K, Ku SL, Meagher A, Hawkins N, Ward R (2003) The relationship between hypomethylation and CpG island methylation in colorectal neoplasia. Am J Pathol 162:1361–1371

  2. 2.

    Bastian PJ, Ellinger J, Wellmann A, Wernert N, Heukamp LC, Muller SC, von Ruecker A (2005) Diagnostic and prognostic information in prostate cancer with the help of a small set of hypermethylated gene loci. Clin Cancer Res 11:4097–4106

  3. 3.

    Bastian PJ, Yegnasubramanian S, Palapattu GS, Rogers CG, Lin X, De Marzo AM, Nelson WG (2004) Molecular biomarker in prostate cancer: the role of CpG island hypermethylation. Eur Urol 46:698–708

  4. 4.

    Bostwick DG, Qian J (2004) High-grade prostatic intraepithelial neoplasia. Mod Pathol 17:360–379

  5. 5.

    Cho NY, Kim BH, Choi M, Yoo EJ, Moon KC, Cho YM, Kim D, Kang GH (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

  6. 6.

    Cravo M, Pinto R, Fidalgo P, Chaves P, Gloria L, Nobre-Leitao C, Costa Mira F (1996) Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma. Gut 39:434–438

  7. 7.

    Eads CA, Danenberg KD, Kawakami K, Saltz LB, Blake C, Shibata D, Danenberg PV, Laird PW (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28:E32

  8. 8.

    Eble JN, Sauter G, Epstein JI, Sesterhenn IA (2004) Pathology and genetics of tumors of the urinary system and male genital organs. IARC, Lyon

  9. 9.

    Ehrlich M, Woods CB, Yu MC, Dubeau L, Yang F, Campan M, Weisenberger DJ, Long T, Youn B, Fiala ES, Laird PW (2006) Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors. Oncogene 25:2636–2645

  10. 10.

    Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21:5400–5413

  11. 11.

    Enokida H, Shiina H, Urakami S, Igawa M, Ogishima T, Li LC, Kawahara M, Nakagawa M, Kane CJ, Carroll PR, Dahiya R (2005) Multigene methylation analysis for detection and staging of prostate cancer. Clin Cancer Res 11:6582–6588

  12. 12.

    Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenisch R (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492

  13. 13.

    Henrique R, Jeronimo C, Teixeira MR, Hoque MO, Carvalho AL, Pais I, Ribeiro FR, Oliveira J, Lopes C, Sidransky D (2006) Epigenetic heterogeneity of high-grade prostatic intraepithelial neoplasia: clues for clonal progression in prostate carcinogenesis. Mol Cancer Res 4:1–8

  14. 14.

    Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826

  15. 15.

    Kang GH, Lee S, Kim JS, Jung HY (2003) Profile of aberrant CpG island methylation along multistep gastric carcinogenesis. Lab Invest 83:519–526

  16. 16.

    Kang GH, Lee S, Lee HJ, Hwang KS (2004) Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia. J Pathol 202:233–240

  17. 17.

    Karpf AR, Matsui S (2005) Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells. Cancer Res 65:8635–8639

  18. 18.

    Kim YI, Giuliano A, Hatch KD, Schneider A, Nour MA, Dallal GE, Selhub J, Mason JB (1994) Global DNA hypomethylation increases progressively in cervical dysplasia and carcinoma. Cancer 74:893–899

  19. 19.

    Lee S, Hwang KS, Lee HJ, Kim JS, Kang GH (2004) Aberrant CpG island hypermethylation of multiple genes in colorectal neoplasia. Lab Invest 84:884–893

  20. 20.

    Linhart HG, Lin H, Yamada Y, Moran E, Steine EJ, Gokhale S, Lo G, Cantu E, Ehrich M, He T, Meissner A, Jaenisch R (2007) Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev 21:3110–3122

  21. 21.

    Maruyama R, Toyooka S, Toyooka KO, Virmani AK, Zochbauer-Muller S, Farinas AJ, Minna JD, McConnell J, Frenkel EP, Gazdar AF (2002) Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features. Clin Cancer Res 8:514–519

  22. 22.

    Mohamed MA, Greif PA, Diamond J, Sharaf O, Maxwell P, Montironi R, Young RA, Hamilton PW (2007) Epigenetic events, remodelling enzymes and their relationship to chromatin organization in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. BJU Int 99:908–915

  23. 23.

    Ogino S, Kawasaki T, Brahmandam M, Cantor M, Kirkner GJ, Spiegelman D, Makrigiorgos GM, Weisenberger DJ, Laird PW, Loda M, Fuchs CS (2006) Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn 8:209–217

  24. 24.

    Rand K, Qu W, Ho T, Clark SJ, Molloy P (2002) Conversion-specific detection of DNA methylation using real-time polymerase chain reaction (ConLight-MSP) to avoid false positives. Methods 27:114–120

  25. 25.

    Sakr WA, Partin AW (2001) Histological markers of risk and the role of high-grade prostatic intraepithelial neoplasia. Urology 57(4 Suppl 1):115–120

  26. 26.

    Schulz WA, Elo JP, Florl AR, Pennanen S, Santourlidis S, Engers R, Buchardt M, Seifert HH, Visakorpi T (2002) Genomewide DNA hypomethylation is associated with alterations on chromosome 8 in prostate carcinoma. Gene Chromosome Canc 35:58–65

  27. 27.

    Virmani AK, Muller C, Rathi A, Zoechbauer-Mueller S, Mathis M, Gazdar AF (2001) Aberrant methylation during cervical carcinogenesis. Clin Cancer Res 7:584–589

  28. 28.

    Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E, Ehrlich M, Laird PW (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33:6823–6836

  29. 29.

    Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793

  30. 30.

    Yamada Y, Jackson-Grusby L, Linhart H, Meissner A, Eden A, Lin H, Jaenisch R (2005) Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci USA 102:13580–13585

  31. 31.

    Yamanaka M, Watanabe M, Yamada Y, Takagi A, Murata T, Takahashi H, Suzuki H, Ito H, Tsukino H, Katoh T, Sugimura Y, Shiraishi T (2003) Altered methylation of multiple genes in carcinogenesis of the prostate. Int J Cancer 106:382–387

Download references

Acknowledgments

This study was supported by the 21C Frontier Functional Human Genome Project from the Ministry of Science & Technology in Korea (FG06-11-02 to G.H.K.) by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0720540) and by the second stage Brain Korea 21 project.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Correspondence to Gyeong Hoon Kang.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary figure

Comparison of the methylation levels of ten genes in three groups of prostatic carcinomas, which were arbitrarily defined by their Gleason scores: tumors with a score ≤3 + 3, tumors with a score of 3 + 4 or 4 + 3, and tumors with a score ≥4 + 4. The examined genes were sorted ordered from highest to lowest P values from left to right along the x axis. Error bar indicates SEM. (DOC 20 KB)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cho, N., Kim, J.H., Moon, K.C. et al. Genomic hypomethylation and CpG island hypermethylation in prostatic intraepithelial neoplasm. Virchows Arch 454, 17–23 (2009). https://doi.org/10.1007/s00428-008-0706-6

Download citation

Keywords

  • CpG island
  • DNA methylation
  • Prostate adenocarcinoma
  • Prostate intraepithelial neoplasm