TY - JOUR T1 - Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation JF - bioRxiv DO - 10.1101/305193 SP - 305193 AU - Arie B. Brinkman AU - Serena Nik-Zainal AU - Femke Simmer AU - F. Germán Rodríguez-González AU - Marcel Smid AU - Ludmil B. Alexandrov AU - Adam Butler AU - Sancha Martin AU - Helen Davies AU - Dominik Glodzik AU - Xueqing Zou AU - Manasa Ramakrishna AU - Johan Staaf AU - Markus Ringnér AU - Anieta Sieuwerts AU - Anthony Ferrari AU - Sandro Morganella AU - Thomas Fleischer AU - Vessela Kristensen AU - Marta Gut AU - Marc J. van de Vijver AU - Anne-Lise Børresen-Dale AU - Andrea L. Richardson AU - Gilles Thomas AU - Ivo G. Gut AU - John W.M. Martens AU - John A. Foekens AU - Mike Stratton AU - Hendrik G. Stunnenberg Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/11/15/305193.abstract N2 - Global loss of DNA methylation and CpG island (CGI) hypermethylation are regarded as key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which can 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. Using whole genome bisulfite sequencing (WGBS) of breast cancers, we comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of variation in DNA methylation. 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). However, significant repression effects on cancer-genes are negligible as tumor suppressor genes are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin of different cancers and may represent tissue-specific ‘silent’ regions of the genome, which tolerate instability at the epigenetic, transcriptomic and genetic level. ER -