A DNA methylation fingerprint of 1628 human samples

  1. Manel Esteller1,28,29,30
  1. 1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, 08908 Barcelona, Catalonia, Spain;
  2. 2Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain;
  3. 3Max-Planck-Institut for Informatics, 66123 Saarbrücken, Germany;
  4. 4Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24118 Kiel, Germany;
  5. 5First Department of Internal Medicine, Sapporo Medical University School of Medicine, 060-8556 Sapporo, Japan;
  6. 6The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
  7. 7Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain;
  8. 8Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;
  9. 9Medizinische Klinik IV, Universitaetsklinikum Aachen, RWTH Aachen, 52074 Aachen, Germany;
  10. 10Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet, CIBERNED, L'Hospitalet, 08908 Barcelona, Catalonia, Spain;
  11. 11Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, 08908 Barcelona, Catalonia, Spain;
  12. 12Biomarkers and Susceptibility Unit, Cancer Prevention and Control Program, Catalan Institute of Oncology, IDIBELL and University of Barcelona, L'Hospitalet, 08908 Barcelona, Catalonia, Spain;
  13. 13Biochemistry and Molecular Biology Department, Alcala University, 28871 Madrid, Spain;
  14. 14Department of Neurosurgery, University of Goettingen, Goettingen WT-084071, Germany;
  15. 15Division of Oncology, Center for Applied Medical Research, University of Navarra, 31080 Pamplona, Spain;
  16. 16Department of Immunology and Oncology, National Center for Biotechnology, CNB-CSIC, Cantoblanco, Madrid E-28049, Spain;
  17. 17Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, E-08003 Barcelona, Spain;
  18. 18Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), E-08003 Barcelona, Catalonia, Spain;
  19. 19Department of Pediatric Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Catalonia, Spain;
  20. 20Melanoma Unit, Dermatology Department, Hospital Clinic, 08036 Barcelona, Catalonia, Spain;
  21. 21Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 08950 Barcelona, Spain;
  22. 22Cardiovascular Research Center, CSIC-ICCC, Hospital Sant Pau, 08025 Barcelona, Catalonia, Spain;
  23. 23Unit of Genetics and Cardiovascular Research Institute, Istituto Ricovero Cura Carattere Scientifico Multimedica, 20099 Sesto S. Giovanni, Italy;
  24. 24Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
  25. 25University College London Cancer Institute, London WC1E 6DD, United Kingdom;
  26. 26Broad Institute, Cambridge, Massachusetts 02142, USA;
  27. 27Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA;
  28. 28Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08908 Barcelona, Catalonia, Spain;
  29. 29Institucio Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain

    Abstract

    Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases.

    Footnotes

    • Received December 23, 2010.
    • Accepted May 23, 2011.

    Freely available online through the Genome Research Open Access option.

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