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Nat Commun. 2019 Apr 15;10(1):1749. doi: 10.1038/s41467-019-09828-0.

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

Author information

1
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, PO Box 9101, Nijmegen, 6500 HB, The Netherlands. a.brinkman@science.ru.nl.
2
Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
3
Academic Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.
4
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, PO Box 9101, Nijmegen, 6500 HB, The Netherlands.
5
Department of Pathology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands.
6
Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, 3015 GD, The Netherlands.
7
Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM, 87545, USA.
8
Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA.
9
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, SE-223 81, Sweden.
10
Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France.
11
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK.
12
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, 0310, Norway.
13
K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, 0316, Norway.
14
Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Division of Medicine, Akershus University Hospital, Lørenskog, 1478, Norway.
15
Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona, Barcelona, 08028, Spain.
16
Department of Pathology, Academic Medical Center, Meibergdreef 9, Amsterdam, AZ 1105, The Netherlands.
17
Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
18
Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
19
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, PO Box 9101, Nijmegen, 6500 HB, The Netherlands. h.stunnenberg@ncmls.ru.nl.

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.

PMID:
30988298
PMCID:
PMC6465362
DOI:
10.1038/s41467-019-09828-0
[Indexed for MEDLINE]
Free PMC Article

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