Journal Article

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

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

2019

Overview

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. In cancer, global DNA methylation loss and CpG island hypermethylation are commonly observed. Here, in breast cancer the authors find that hyper-variability of partially methylated domains is the prime source of DNA methylation variation and that these domains fuel CpG island hypermethylation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/91 / 45/23 / 49/39 / 60 APPLIED LIFE SCIENCES / 631/337/176/1988 / 631/67/69 / Basic Medicine / Breast cancer / Breast Neoplasms - genetics / Cancer / Cancer and Oncology / Cancer och onkologi / Cell and Molecular Biology / Cell- och molekylärbiologi / Clinical Medicine / CpG Islands / Deoxyribonucleic acid / DNA / DNA Methylation / Domains / Epigenesis, Genetic / Epigenetics / Female / Genomes / Genomics / Humanities and Social Sciences / Humans / Klinisk medicin / Life Sciences / Logistic Models / Medical and Health Sciences / Medicin och hälsovetenskap / Medicinska och farmaceutiska grundvetenskaper / multidisciplinary / Mutation / Mutation rates / Phenotypes / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Stability / Tumor suppressor genes / Tumors