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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Arie B. Brinkman
  • Serena Nik-Zainal
  • Femke Simmer
  • F. Germán Rodríguez-González
  • Marcel Smid
  • Ludmil B. Alexandrov
  • Adam Butler
  • Sancha Martin
  • Helen Davies
  • Xueqing Zou
  • Manasa Ramakrishna
  • Anieta Sieuwerts
  • Anthony Ferrari
  • Sandro Morganella
  • Thomas Fleischer
  • Vessela Kristensen
  • Marta Gut
  • Marc J. van de Vijver
  • Anne Lise Børresen-Dale
  • Andrea L. Richardson
  • Gilles Thomas
  • Ivo G. Gut
  • John W.M. Martens
  • John A. Foekens
  • Michael R. Stratton
  • Hendrik G. Stunnenberg
Organisations
External organisations
  • Radboud University Nijmegen
  • Wellcome Trust Sanger Institute
  • University of Cambridge
  • Erasmus University Medical Center
  • Los Alamos National Laboratory
  • Centre Léon Bérard
  • Wellcome Trust Genome Campus
  • Norwegian Radium Hospital
  • University of Oslo
  • Akershus University Hospital
  • University of Barcelona
  • Academic Medical Center of University of Amsterdam (AMC)
  • Brigham and Women's Hospital / Harvard Medical School
  • Dana-Farber Cancer Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Cancer and Oncology
Original languageEnglish
Article number1749
JournalNature Communications
Volume10
Issue number1
Publication statusPublished - 2019 Apr 15
Publication categoryResearch
Peer-reviewedYes