This study investigates the patterns and dynamics of genomic instability in metastatic pancreatic cancer. Researchers analyzed 13 patients with pancreatic cancer, identifying somatic and germline genomic rearrangements. They found that pancreatic cancer often involves genomic instability, including telomere dysfunction and abnormal cell-cycle control, which may initiate cancer gene amplification. These genomic instabilities persist after cancer dissemination, leading to ongoing, parallel, and even convergent evolution among different metastases. The study also reveals genetic heterogeneity among metastasis-initiating cells, suggesting that seeding metastasis may require driver mutations beyond those needed for primary tumours. Phylogenetic trees across metastases show organ-specific branches, indicating that certain genetic changes may drive metastasis to specific organs. The study used massively parallel paired-end sequencing to identify somatically acquired genomic rearrangements. They found that genomic instability in pancreatic cancer is characterized by specific abnormalities in cell-cycle control, such as dysregulation of the G1-to-S transition and an intact G2–M checkpoint. These instabilities are often caused by breakage-fusion-bridge cycles, which may result from telomere loss. The distribution of rearrangements in pancreatic cancer differs from that in breast cancer, with more frequent deletions and fold-back inversions in pancreatic cancer. The study also found evidence of clonal evolution within tumours and metastases. Some rearrangements are present in all metastases and the primary tumour, while others are unique to specific metastases. This suggests that metastasis is clonal, with individual deposits seeded by one or a few genetically similar cells. The study also found that some rearrangements occur throughout the cancer life cycle, although the biological pathways underlying these forms of genomic instability remain unclear. The findings highlight the complexity of genomic instability in pancreatic cancer and its role in metastasis. The study provides insights into the genetic diversity and adaptability of cancer under different selection pressures, which has implications for the development of curative therapies for metastatic disease. The ability to identify and understand early mutations in cancer provides a route to the discovery of drug targets.This study investigates the patterns and dynamics of genomic instability in metastatic pancreatic cancer. Researchers analyzed 13 patients with pancreatic cancer, identifying somatic and germline genomic rearrangements. They found that pancreatic cancer often involves genomic instability, including telomere dysfunction and abnormal cell-cycle control, which may initiate cancer gene amplification. These genomic instabilities persist after cancer dissemination, leading to ongoing, parallel, and even convergent evolution among different metastases. The study also reveals genetic heterogeneity among metastasis-initiating cells, suggesting that seeding metastasis may require driver mutations beyond those needed for primary tumours. Phylogenetic trees across metastases show organ-specific branches, indicating that certain genetic changes may drive metastasis to specific organs. The study used massively parallel paired-end sequencing to identify somatically acquired genomic rearrangements. They found that genomic instability in pancreatic cancer is characterized by specific abnormalities in cell-cycle control, such as dysregulation of the G1-to-S transition and an intact G2–M checkpoint. These instabilities are often caused by breakage-fusion-bridge cycles, which may result from telomere loss. The distribution of rearrangements in pancreatic cancer differs from that in breast cancer, with more frequent deletions and fold-back inversions in pancreatic cancer. The study also found evidence of clonal evolution within tumours and metastases. Some rearrangements are present in all metastases and the primary tumour, while others are unique to specific metastases. This suggests that metastasis is clonal, with individual deposits seeded by one or a few genetically similar cells. The study also found that some rearrangements occur throughout the cancer life cycle, although the biological pathways underlying these forms of genomic instability remain unclear. The findings highlight the complexity of genomic instability in pancreatic cancer and its role in metastasis. The study provides insights into the genetic diversity and adaptability of cancer under different selection pressures, which has implications for the development of curative therapies for metastatic disease. The ability to identify and understand early mutations in cancer provides a route to the discovery of drug targets.