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Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation

Author

Listed:
  • Arie B. Brinkman

    (Radboud University)

  • Serena Nik-Zainal

    (Wellcome Trust Sanger Institute
    University of Cambridge)

  • Femke Simmer

    (Radboud University
    Radboud University Nijmegen Medical Centre)

  • F. Germán Rodríguez-González

    (Erasmus University Medical Center)

  • Marcel Smid

    (Erasmus University Medical Center)

  • Ludmil B. Alexandrov

    (Wellcome Trust Sanger Institute
    Los Alamos National Laboratory
    Los Alamos National Laboratory)

  • Adam Butler

    (Wellcome Trust Sanger Institute)

  • Sancha Martin

    (Wellcome Trust Sanger Institute)

  • Helen Davies

    (Wellcome Trust Sanger Institute)

  • Dominik Glodzik

    (Wellcome Trust Sanger Institute)

  • Xueqing Zou

    (Wellcome Trust Sanger Institute)

  • Manasa Ramakrishna

    (Wellcome Trust Sanger Institute)

  • Johan Staaf

    (Lund University)

  • Markus Ringnér

    (Lund University)

  • Anieta Sieuwerts

    (Erasmus University Medical Center)

  • Anthony Ferrari

    (Synergie Lyon Cancer, Centre Léon Bérard)

  • Sandro Morganella

    (Wellcome Trust Genome Campus)

  • Thomas Fleischer

    (Oslo University Hospital, The Norwegian Radium Hospital)

  • Vessela Kristensen

    (Oslo University Hospital, The Norwegian Radium Hospital
    University of Oslo
    Akershus University Hospital)

  • Marta Gut

    (Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona)

  • Marc J. Vijver

    (Academic Medical Center)

  • Anne-Lise Børresen-Dale

    (Oslo University Hospital, The Norwegian Radium Hospital
    University of Oslo)

  • Andrea L. Richardson

    (Brigham and Women’s Hospital
    Dana-Farber Cancer Institute)

  • Gilles Thomas

    (Synergie Lyon Cancer, Centre Léon Bérard)

  • Ivo G. Gut

    (Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona)

  • John W. M. Martens

    (Erasmus University Medical Center)

  • John A. Foekens

    (Erasmus University Medical Center)

  • Michael R. Stratton

    (Wellcome Trust Sanger Institute)

  • Hendrik G. Stunnenberg

    (Radboud University)

Abstract

Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.

Suggested Citation

  • Arie B. Brinkman & Serena Nik-Zainal & Femke Simmer & F. Germán Rodríguez-González & Marcel Smid & Ludmil B. Alexandrov & Adam Butler & Sancha Martin & Helen Davies & Dominik Glodzik & Xueqing Zou & M, 2019. "Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09828-0
    DOI: 10.1038/s41467-019-09828-0
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