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

Brinkman, Arie B.; Nik-Zainal, Serena; Simmer, Femke; Rodríguez-González, F. Germán; Smid, Marcel; Alexandrov, Ludmil B.; Butler, Adam; Martin, Sancha; Davies, Helen; Glodzik, Dominik; Zou, Xueqing; Ramakrishna, Manasa; Staaf, Johan; Ringnér, Markus; Sieuwerts, Anieta; Ferrari, Anthony; Morganella, Sandro; Fleischer, Thomas; Kristensen, Vessela; Gut, Marta; van de Vijver, Marc J.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Thomas, Gilles; Gut, Ivo G.; Martens, John W.  M.; Foekens, John A.; Stratton, Michael R.; Stunnenberg, Hendrik G.

doi:10.1038/s41467-019-09828-0

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

Journal Article · Mon Apr 15 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-09828-0· OSTI ID:1624152

^[1]; Nik-Zainal, Serena ^[2]; Simmer, Femke ^[3]; Rodríguez-González, F. Germán ^[4]; Smid, Marcel ^[4]; Alexandrov, Ludmil B. ^[5]; Butler, Adam ^[6]; ^[6]; Davies, Helen ^[6]; Glodzik, Dominik ^[6]; Zou, Xueqing ^[6]; Ramakrishna, Manasa ^[6]; ^[7]; ^[7]; ^[4]; Ferrari, Anthony ^[8]; Morganella, Sandro ^[9]; ^[10]; Kristensen, Vessela ^[11]; Gut, Marta ^[12] more »

Radboud Univ., Nijmegen (Netherlands). Radboud Inst. for Molecular Life Sciences. Faculty of Science. Dept. of Molecular Biology; DOE/OSTI
Wellcome Trust Sange Inst., Cambridge (United Kingdom); Univ. of Cambridge (United Kingdom). Academic Dept. of Medical Genetics
Radboud Univ., Nijmegen (Netherlands). Radboud Inst. for Molecular Life Sciences. Faculty of Science. Dept. of Molecular Biology
Erasmus Univ. Medical Center, Rotterdam (Netherlands). Erasmus MC Cancer Inst. and Cancer Genomics Netherlands
Wellcome Trust Sange Inst., Cambridge (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics; Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Center for Nonlinear Studies
Wellcome Trust Sange Inst., Cambridge (United Kingdom)
Lund Univ. (Sweden). Dept. of Clinical Sciences Lund. Division of Oncology and Pathology
Centre Léon Bérard, Lyon (France). Synergie Lyon Cancer
Wellcome Trust Genome Campus, Hinxton (United Kingdom). European Bioinformatics Inst. European Molecular Biology Lab.
The Norwegian Radium Hospital (Norway). Oslo Univ. Hospital. Inst. for Cancer Research. Dept. of Genetics
The Norwegian Radium Hospital (Norway). Oslo Univ. Hospital. Inst. for Cancer Research. Dept. of Genetics; Univ. of Oslo (Norway). Inst. for Clinical medicine. K.G. Jebsen Centre for Breast Cancer Research; Akerhus Univ. Hospital, Lørenskog (Norway). Division of Medicine. Dept. of Clinical moelcular Biology and Lab. Science (EpiGen)
Parc Cientific de Barcelona (Spain). Centro nacional de Análisis Genómico (CNAG)
Academic Medical Center, Amsterdam (Netherlands). Dept. of Pathology
The Norwegian Radium Hospital (Norway). Oslo Univ. Hospital. Inst. for Cancer Research. Dept. of Genetics; Univ. of Oslo (Norway). Inst. for Clinical medicine. K.G. Jebsen Centre for Breast Cancer Research
Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States). Dept. of Pathology; Dana-Farber Cancer Institute, Boston, MA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1624152

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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