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DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Batra, Rajbir Nath 
Lifshitz, Aviezer 
Vidakovic, Ana Tufegdzic 
Sati-Batra, Ankita 

Abstract

DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

Description

Keywords

Breast Neoplasms, Cohort Studies, CpG Islands, DNA Methylation, DNA Replication, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Genomic Instability, Genomics, Humans, MCF-7 Cells, Mutation, Promoter Regions, Genetic, Survival Analysis

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

12

Publisher

Nature Research
Sponsorship
European Research Council (694620)
Wellcome Trust (106566/Z/14/Z)
Cancer Research UK (C9545/A29580_do not transfer)
Cancer Research UK (25815)
Cancer Research UK (C14303/A17197)
Medical Research Council (MR/P012442/1)
Cancer Research UK (16942)