Abstract

Human cancers are characterised by markedly disordered genomic architecture, driven by genomic instability. We harnessed advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer, unlike breast cancer, acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-S phase transition with intact G2-M checkpoint. These occurred early in cancer development and initiated amplification of cancer genes. Genomic instability frequently continued after cancer dissemination, resulting in on-going, parallel and even convergent evolution among different metastases. We find evidence that secondary metastases can themselves seed tertiary metastases; initiating metastasis may require mutations beyond those required for primary tumours; and phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, hewn by the tandem forces of genomic instability and evolutionary selection.