Aberrant CpG-island methylation has non-random and tumour-type–specific patterns (original) (raw)

Nature Genetics volume 24, pages 132–138 (2000)Cite this article

Abstract

CpG islands frequently contain gene promoters or exons1 and are usually unmethylated in normal cells1,2,3. Methylation of CpG islands is associated with delayed replication, condensed chromatin and inhibition of transcription initiation4,5,6,7. The investigation of aberrant CpG-island methylation in human cancer has primarily taken a candidate gene approach, and has focused on less than 15 of the estimated 45,000 CpG islands8 in the genome. Here we report a global analysis of the methylation status of 1,184 unselected CpG islands in each of 98 primary human tumours using restriction landmark genomic scanning9 (RLGS). We estimate that an average of 600 CpG islands (range of 0 to 4,500) of the 45,000 in the genome were aberrantly methylated in the tumours, including early stage tumours. We identified patterns of CpG-island methylation that were shared within each tumour type, together with patterns and targets that displayed distinct tumour-type specificity. The expression of many of these genes was reactivated by experimental demethylation in cultured tumour cells. Thus, the methylation of particular subsets of CpG islands may have consequences for specific tumour types.

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Acknowledgements

We thank M.S. Berger, A. Asai, A. Tamura and N. Shitara for glioma samples; S. Edge and E. Repasky for help in obtaining primary breast tumour tissue; R. Lothe for testicular tumours, T. Weber and M.A. Rodriguez-Bigas for colon tumour samples; B. Chadwick and J. Weger for nucleotide sequencing; B. Yuan for the automated sequence analysis; J. Eisel, A. Morrow, J. Popovich and Y.-Z. Wu for technical assistance; C. DeSmet for helpful discussions; and Y. Hayashizaki and the late V. Chapman for advice and encouragement. We thank the Cooperative Human Tissue Network (CHTN) Midwestern Division and the CALGB Leukemia Tissue Bank for providing tissue samples. This work was supported in part by the National Cancer Institute grant P30 CA16058 and CA80912 (to C.P.), the Coleman Leukemia Research Foundation grant 3U10CA31946-17S3, the Children's Hospital Research Foundation grant 216398, the Ladies Auxiliary of the Veterans of Foreign Wars grant 216498 and the Roswell Park Alliance Foundation. D.J.S. was supported by the Corixa Corporation and the T32 CA09338-20 Oncology Training Grant from the National Cancer Institute. M.C.F. was supported by a fellowship of the Dr. Mildred Scheel Stiftung für Krebsforschung/Deutsche Krebshilfe. J.F.C. was supported sequentially by the Basic Science Fellowship from the American Association for Cancer Research and by the Frances Goodrich and Albert Hackett Postdoctoral Fellowship from the American Brain Tumor Association.

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Author notes

  1. Joseph F. Costello
    Present address: University of California, San Francisco, California, USA

Authors and Affiliations

  1. Ludwig Institute for Cancer Research,
    Joseph F. Costello, Gavin P. Robertson, Jamison D. Feramisco, H.-J. Su Huang & Webster K. Cavenee
  2. Department of Medicine,
    H.-J. Su Huang & Webster K. Cavenee
  3. Center for Molecular Genetics, University of California-San Diego, La Jolla, California, USA
    Webster K. Cavenee
  4. Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics,
    Michael C. Frühwald, Dominic J. Smiraglia, Laura J. Rush, Xin Gao, Fred A. Wright, Päivi Peltomäki & Christoph Plass
  5. Department of Veterinary Biosciences,
    Laura J. Rush
  6. Department of Otolaryngology,
    James C. Lang & David E. Schuller
  7. Division of Hematology and Oncology, Department of Internal Medicine,
    Li Yu, Clara D. Bloomfield & Michael A. Caligiuri
  8. Department of Pathology,
    Allan Yates
  9. Department of Neuroscience and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
    Michael C. Frühwald
  10. Department of Pediatrics, Children's Hospital, Columbus, Ohio, USA
    Michael C. Frühwald & M. S. O'Dorisio
  11. Department of Neurosurgery, Saitama Medical School, Moroyama-machi, Iruma-gun, Saitama-ken, Japan
    Ryo Nishikawa
  12. Department of Surgical Oncology,
    Nicholas J. Petrelli
  13. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA
    Xueli Zhang & William A. Held

Authors

  1. Joseph F. Costello
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  2. Michael C. Frühwald
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  3. Dominic J. Smiraglia
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  4. Laura J. Rush
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  5. Gavin P. Robertson
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  6. Xin Gao
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  7. Fred A. Wright
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  8. Jamison D. Feramisco
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  9. Päivi Peltomäki
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  10. James C. Lang
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  11. David E. Schuller
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  12. Li Yu
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  13. Clara D. Bloomfield
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  14. Michael A. Caligiuri
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  15. Allan Yates
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  16. Ryo Nishikawa
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  17. H.-J. Su Huang
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  18. Nicholas J. Petrelli
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  19. Xueli Zhang
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  20. M. S. O'Dorisio
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  21. William A. Held
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  22. Webster K. Cavenee
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  23. Christoph Plass
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Corresponding authors

Correspondence toJoseph F. Costello or Christoph Plass.

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Costello, J., Frühwald, M., Smiraglia, D. et al. Aberrant CpG-island methylation has non-random and tumour-type–specific patterns.Nat Genet 24, 132–138 (2000). https://doi.org/10.1038/72785

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