Abstract
Highlights
Replication timing alterations are conserved in cancers of different cell origins
Long-range epigenetic deregulation in cancer involves altered replication timing
Cancer late-replicating loci are hypomethylated and acquire facultative heterochromatin
Replication timing status potentiates cis and trans chromosomal rearrangements
Summary Replication timing is known to facilitate the establishment of epigenome, however, the intimate connection between DNA replication timing and changes to the genome and epigenome in cancer remain uncharted. Here, we perform Repli-Seq and integrated epigenome analysis and show that early-replicating loci are predisposed to hypermethylation and late-replicating loci to hypomethylation, enrichment of H3K27me3 and concomitant loss of H3K9me3. We find that altered replication timing domains correspond to long-range epigenetically deregulated regions in prostate cancer, and a subset of these domains are remarkably conserved across cancers from different tissue origins. Analyses of 214 prostate and 35 breast cancer genomes reveal that late-replicating DNA is prone to cis and early-replicating DNA to trans chromosomal rearrangements. We propose that differences in epigenetic deregulation related to spatial and temporal positioning between early and late replication potentiate the landscape of chromosomal rearrangements in cancer.