Abstract
Medulloblastomas exhibit an array of diverse cytogenetic abnormalities. To evaluate the significance of epigenetic rather than genetic lesions in medulloblastomas and other primitive neuroectodermal tumors (PNETs) of the childhood CNS we performed a systematic analysis of gene specific and global methylation. Methylation-specific PCR detected no methylation for p15INK4B, von Hippel Lindau and TP53 and only limited methylation for E-Cadherin and p16INK4A in tumors. The cell lines Daoy and MHH-PNET-5 in which the p16INK4A promoter was methylated did not express the gene, but demonstrated abnormalities by SSCP. Immunohistochemistry for p16 was negative in all examined normal cerebella and medulloblastomas. Using the technique of Restriction Landmark Genomic Scanning we detected methylation affecting up to 1% of all CpG islands in primary MB/PNETs and 6% in MB cell lines. Methylation patterns differed between medulloblastomas and PNETs. Examination of several methylated sequences revealed homologies to known genes and expressed sequences. Analysis of survival data identified seven of 30 hypermethylated sequences significantly correlating with poor prognosis. We suggest that DNA hypermethylation has an outstanding potential for the identification of novel tumor suppressors as well as diagnostic and therapeutic targets in MBs and other PNETs of the CNS.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aldosari N, Rasheed BK, McLendon RE, Friedman HS, Bigner DD, Bigner SH . 2000 Acta. Neuropathol. (Berl) 99: 345–351
Barker FG, Chen P, Furman F, Aldape KD, Edwards MS, Israel MA . 1997 J. Neurooncol. 31: 17–23
Baylin SB, Herman JG . 2000 Trends Genet. 16: 168–174
Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP . 1998 Adv. Cancer Res. 72: 141–196
Burnett ME, White EC, Sih S, von Haken MS, Cogen PH . 1997 Cancer Genet. Cytogenet. 97: 25–31
Burns KL, Ueki K, Jhung SL, Koh J, Louis DN . 1998 J. Neuropathol. Exp. Neurol. 57: 122–130
Consortium IHGS . 2001 Nature 860: 860–921
Costello JF, Frühwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O'Dorisio MS, Held WA, Cavenee WK, Plass C . 2000 Nat. Genet. 24: 132–138
David KM, Casey AT, Hayward RD, Harkness WF, Phipps K, Wade AM . 1997 J. Neurosurg. 86: 13–21
Frühwald MC, O'Dorisio MS, Dai Z, Rush LJ, Krahe R, Smiraglia DJ, Pietsch T, Elsea SH, Plass C . 2001 Genes Chromo. Cancer 30: 38–47
Frühwald MC, O'Dorisio MS, Dai Z, Smiraglia DJ, Plass C . 1999 Neurooncology 1: 311
Frühwald MC, O'Dorisio MS, Rush LJ, Reiter JL, Smiraglia DJ, Wenger G, Costello JF, White PS, Krahe R, Brodeur GM, Plass C . 2000 J. Med. Genet. 37: 501–509
Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB . 1995 Cancer Res. 55: 5195–5199
Grotzer MA, Janss AJ, Fung K, Biegel JA, Sutton LN, Rorke LB, Zhao H, Cnaan A, Phillips PC, Lee VM, Trojanowski JQ . 2000 J. Clin. Oncol. 18: 1027–1035
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . 1996 Proc. Natl. Acad. Sci. USA 93: 9821–9826
Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM. et al . 1994 Proc. Natl. Acad. Sci. USA 91: 9700–9704
Jen J, Harper JW, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW, Vogelstein B . 1994 Cancer Res. 54: 6353–6358
Jones PA, Laird PW . 1999 Nat. Genet. 21: 163–167
Kalbfleisch JD, Prentice RL . 1984 The Statistical Analysis of Failure Time Data Wiley: New York
Lescop S, Lellouch-Tubiana A, Vassal G, Besnard-Guerin C . 1999 J. Neurooncol. 44: 119–127
Liechti-Gallati S, Schneider V, Neeser D, Kraemer R . 1999 Eur. J. Hum. Genet. 7: 590–598
Litofsky NS, Hinton D, Raffel C . 1994 Neurosurgery 34: 967–972
Marino S, Vooijs M, vanDer Gulden H, Jonkers J, Berns A . 2000 Genes Dev. 14: 994–1004
Mulhern RK, Reddick WE, Palmer SL, Glass JO, Elkin TD, Kun LE, Taylor J, Langston J, Gajjar A . 1999 Ann. Neurol. 46: 834–841
Packer RJ . 1999 Brain Dev. 21: 75–81
Plass C, Weichenhan D, Catanese J, Costello JF, Yu F, Yu L, Smiraglia D, Cavenee WK, Caligiuri MA, de Jong P, Held WA . 1997 DNA Res. 4: 253–255
Reardon DA, Michalkiewicz E, Boyett JM, Sublett JE, Entrekin RE, Ragsdale ST, Valentine MB, Behm FG, Li H, Heideman RL, Kun LE, Shapiro DN, Look AT . 1997 Cancer Res. 57: 4042–4047
Rorke LB, Trojanowski JQ, Lee VM, Zimmerman RA, Sutton LN, Biegel JA, Goldwein JW, Packer RJ . 1997 Brain Pathol. 7: 765–784
Russo C, Pellarin M, Tingby O, Bollen AW, Lamborn KR, Mohapatra G, Collins VP, Feuerstein BG . 1999 Cancer 86: 331–339
Sambrook J, Fritsch E, Maniatis T . 1989 Molecular cloning: A laboratory manual, 2nd edn Cold Spring Harbor Lab Press: Plainview, NY
Sato K, Schauble B, Kleihues P, Ohgaki H . 1996 Int. J. Cancer 66: 305–308
Scheurlen WG, Schwabe GC, Joos S, Mollenhauer J, Sorensen N, Kuhl J . 1998 J. Clin. Oncol. 16: 2478–2485
Scheurlen WG, Seranski P, Mincheva A, Kuhl J, Sorensen N, Krauss J, Lichter P, Poustka A, Wilgenbus KK . 1997 Genes Chromo. Cancer 18: 50–58
Schwechheimer K, Zhou L, Birchmeier W . 1998 Virchows Arch. 432: 163–167
Smiraglia DJ, Frühwald MC, Costello JF, McCormick SP, O'Dorisio MS, Cavanee WK, Plass C . 1999 Genomics 58: 254–262
Sommer A, Waha A, Tonn J, Sorensen N, Hurlin PJ, Eisenman RN, Luscher B, Pietsch T . 1999 Int. J. Cancer 82: 810–816
Tanner SM, Laporte J, Guiraud-Chaumeil C, Liechti-Gallati S . 1998 Hum. Mutat. 11: 62–68
Venter JC et al . 2001 Science 291: 1304–1350
Zurawel RH, Allen C, Wechsler-Reya R, Scott MP, Raffel C . 2000 Genes Chromo. Cancer 28: 77–81
Acknowledgements
We thank Dr T Pietsch (University of Bonn) for the gift of the cell lines MHH-MED-1 and MHH-PNET-5, and Julia Hall, Yue-Zhong Wu and Birgit Kallinger for expert technical assistance. Tissue samples were provided by the Cooperative Human Tissue Network (CHTN) funded by the National Cancer Institute. This work was supported in part by the Children's Hospital Research Foundation grant #216398, by grant #216498 from Ladies Auxiliary of the Veterans of Foreign Wars (MS O'Dorisio), by the National Cancer Institut (Bethesda, MD, USA) grant P30 CA16058, the Bremer Foundation (C Plass) and by grants of the Deutsche Krebshilfe (www.krebshilfe.de) 10-1699-Fr 1, the Deutsche Forschungsgemeinschaft FR 1516/1-1 and the IMF FR 129918 (MC Frühwald). MC Frühwald is the recipient of a fellowship of the Bauer-Stiftung in Stifterverband für die Deutsche Wissenschaft.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Frühwald, M., O'Dorisio, M., Dai, Z. et al. Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas–Implications for tumor biology and potential clinical utility. Oncogene 20, 5033–5042 (2001). https://doi.org/10.1038/sj.onc.1204613
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204613
Keywords
This article is cited by
-
Deregulated proliferation and differentiation in brain tumors
Cell and Tissue Research (2015)
-
Epigenetic repression of the dopamine receptor D4 in pediatric tumors of the central nervous system
Journal of Neuro-Oncology (2014)
-
Aberrant MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation in choroid plexus tumors
Journal of Neuro-Oncology (2009)
-
SGNE1/7B2 is epigenetically altered and transcriptionally downregulated in human medulloblastomas
Oncogene (2007)