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Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas–Implications for tumor biology and potential clinical utility

Oncogene volume 20, pages 5033–5042 (2001)Cite this article

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.

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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.

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Author notes

  1. M Sue O'Dorisio

    Present address: Department of Pediatric Hematology and Oncology, The University of Iowa, Iowa City, 52242, Iowa, USA

Authors and Affiliations

  1. Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Columbus, 43210, Ohio, OH, USA

    Michael C Frühwald, Zunyan Dai, Stephan M Tanner, Xin Gao, Fred A Wright & Christoph Plass

  2. Department of Pediatrics, Children's Hospital, Columbus, 43205, Ohio, OH, USA

    Michael C Frühwald, M Sue O'Dorisio & Douglas A Balster

  3. Department of Pathology and the Comprehensive Cancer Center, The Ohio State University, Columbus, 43210, Ohio, OH, USA

    Zunyan Dai & Douglas A Balster

  4. Westfälische Wilhelms Universität Münster, Klinik und Poliklinik für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, Münster, 48149, Germany

    Michael C Frühwald

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Correspondence to Michael C Frühwald or Christoph Plass.

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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

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