The patterns and dynamics of genomic instability in metastatic pancreatic cancer

摘要: Christine Iacobuzio-Donahue and colleagues use whole-genome exome sequencing to analyse primary pancreatic cancers one or more metastases from the same patients, find that tumours are composed of distinct subclones. The authors also determine evolutionary maps by which metastatic cancer clones have evolved within tumour, estimate timescales tumour progression. On basis these data, they a mean period 11.8 years between initiation tumorigenesis formation parental, non-metastatic further 6.8 for index metastasis clone arise. These data point potentially large window opportunity during it might be possible detect in relatively early form. Peter Campbell next-generation chromosomal rearrangements 13 patients with cancer. results reveal considerable inter-patient heterogeneity indicate ongoing genomic instability evolution development metastases. But most studied, than half genetic found were present all making them potential targets therapeutic intervention at late stages disease. Pancreatic is highly aggressive, usually because widespread metastasis. Here, DNA has been used explore clonal relationships among not only heterogeneity, but an aggressive malignancy five-year mortality 97–98%, due Previous studies this disease complex landscape, frequent copy number changes mutations1,2,3,4,5, characterized detail. Despite clinical importance metastasis, there remain fundamental questions about structures tumours6,7, including phylogenetic metastases, scale parallel sites7, how disseminates. Here we harness advances sequencing8,9,10,11,12 annotate We acquires indicative telomere dysfunction abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition intact G2–M checkpoint. initiate amplification genes occur predominantly rather later Genomic frequently persists after dissemination, resulting ongoing, even convergent different evidence metastasis-initiating cells, seeding may require driver mutations beyond those required tumours, trees across show organ-specific branches. attest richness variation cancer, brought tandem forces selection.