DNA replication timing is known to facilitate the establishment of the epigenome, however, the intimate connection between replication timing and changes to the genome and epigenome in cancer remain largely uncharacterised. Here, we perform Repli-Seq and integrated epigenome analyses and demonstrate that genomic regions that undergo long-range epigenetic deregulation in prostate cancer also show concordant differences in replication timing. A subset of altered replication timing domains are conserved across cancers from different tissue origins. Notably, late-replicating regions in cancer cells display a loss of DNA methylation, and a switch in heterochromatin features from H3K9me3-marked constitutive to H3K27me3-marked facultative heterochromatin. Finally, analysis of 214 prostate and 35 breast cancer genomes reveal that late-replicating regions are prone to cis and early-replication to trans chromosomal rearrangements. Together, our data suggests that the nature of chromosomal rearrangement in cancer is related to the spatial and temporal positioning and altered epigenetic states of early-replicating compared to late-replicating loci.

ASMT is a key determinant of the levels of released melatonin. Though melatonin has been shown to exhibit anti-cancer activity and prevents endocrine resistance in breast cancer, the role of ASMT in breast cancer progression remains unclear. In this retrospective study, we analyzed gene expression profiles from thousands of patients and found that ASMT expression was significantly lower in breast cancer tumors relative to healthy tissue. Among cancer patients, those with greater expression had better relapse-free survival outcomes and longer metastasisfree survival times, and they also experienced longer periods before relapse or distance recurrence following tamoxifen treatment. Administration of melatonin, in combination with tamoxifen, further promoted cancer cell death by promoting apoptosis. Motivated by these results, we devised an ASMT gene signature that identifies low-risk cases with great accuracy.This signature was validated using both mRNA array and RNAseq datasets. Intriguingly, patients who are classified as high-risk benefit from adjuvant chemotherapy, and those with grade II tumors who are classified as low-risk exhibit improved overall survival and distance relapse-free outcomes following endocrine therapy. Our findings more clearly elucidate the roles of ASMT, provide strategies for improving the efficacy of tamoxifen treatment, and help to identify those patients who may maximally benefit from adjuvant or endocrine therapies. in breast tumors, and elevated levels of ASMT expression improve relapse-free survival (RFS) outcomes and metastasis-free survival times. Relative to other breast cancer patients, those with relatively higher expression levels of ASMT exhibit fewer relapses or longer distance recurrence outcomes following tamoxifen treatment. Administration of melatonin, in combination with tamoxifen, further promotes cancer cell death by upregulating apoptosis. Furthermore, we also devise a novel gene signature that can robustly predict recurrence risk. Patients predicted to be high-risk benefitted significantly from adjuvant chemotherapy. In addition, following endocrine therapy, low-risk patients benefited from better overall survival and distance relapse-free outcomes. 5 Materials and methodsCell culture preparation MCF7 cells were grown to 70% confluence in phenol-red-free RPMI 1640 supplemented with 10% fetal bovine serum, 100 units/ml penicillin and 100 μ g/ml streptomycin sulfate at 37°C in a humidified 5% CO2 environment. Cells were pretreated with 1.0 mM melatonin for 2h then treated with 2.5 µM 4-OHT for 24h. Melatonin and 4-OHT were freshly prepared in a 1000X stock solution in DMSO and then diluted to the desired concentration directly in the culture medium. DMSO was added to control groups in each experiment. Live cells were observed under a Nikon Eclipse TE200 inverted microscope (Nikon, Tokyo, Japan). Cell apoptosis assaysThe apoptotic cell distribution was evaluated using the Muse Annexin V & Dead Cell Kit from Merck Millipore (Danvers, MA, USA) per the manufacturer's inst...