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

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, Manasa Ramakrishna, Johan Staaf, Markus Ringnér, Anieta Sieuwerts, Anthony Ferrari, Sandro Morganella, Thomas Fleischer, Vessela Kristensen, Marta Gut, Marc J. Vijver, Anne-Lise Børresen-Dale, Andrea L. Richardson, Gilles Thomas, Ivo G. Gut, John W. M. Martens, John A. Foekens, Michael R. Stratton and Hendrik G. Stunnenberg ()
Additional contact information
Arie B. Brinkman: Radboud University
Serena Nik-Zainal: Wellcome Trust Sanger Institute
Femke Simmer: Radboud University
F. Germán Rodríguez-González: Erasmus University Medical Center
Marcel Smid: Erasmus University Medical Center
Ludmil B. Alexandrov: Wellcome Trust Sanger Institute
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
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
Andrea L. Richardson: Brigham and Women’s Hospital
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

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09828-0

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