Cell type-specific DNA replication initiation and termination in human primary cancer whole genomes

The understanding of where exactly, and how differently, DNA replication starts and ends in the cancer genomes remain limited. Although DNA sequences that underwent somatic alterations across human primary cancers have been comprehensively studied, the entire accurately replicated sequences of the same primary cancer genomes have not been widely explored. Here, we present a novel in silico framework to assess the tumour replication timing (RT) programme directly using 256 primary cancer whole genomes across three tumour types. We introduce a novel bootstrap-based replication fork directionality (RFD) method to model the bi-directional replication, and simultaneously map the replication origin and terminus domains at 1 kb resolution. Unexpectedly, our high-resolution results suggest that the genome-wide distribution of termination zones (TZs) is tightly coordinated with the initiation zones (IZs) in both normal and cancer genomes, which has not been previously reported using in vitro directional sequencing of Okazaki fragments (OK-seq) method. Overall, our data demonstrate that the cell type specificity of the tumour replication timing domains is preserved in closely related normal tissues and in lineage-specific cancer cell lines. Finally, comparing altered replication initiations between normal and cancer genomes, our data identifies delocalisation of replication initiations near highly expressed proliferation-associated PIF1 gene in small cell lung cancer (SCLC) genome, suggesting a potential cancer-specific target.