Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97–98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations1,2,3,4,5, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours6,7, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites7, and how the tumour disseminates. Here we harness advances in DNA sequencing8,9,10,11,12 to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2–M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.
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Genome sequence data have been deposited at the European Genome-Phenome Archive (EGA, http://www.ebi.ac.uk/ega/), which is hosted by the European Bioinformatics Institute (EBI), under accession number EGAS00000000064.
This work was supported by the Wellcome Trust (grant reference 077012/Z/05/Z). P.J.C. is funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). S.Y. has support from the Uehara memorial foundation. We would also like to acknowledge the financial support of the Skip Viragh Foundation and the Michael Rolphe Foundation for the autopsy programme, and funding from the National Institutes of Health (grants CA106610 and CA140599). I.V. is supported by a fellowship from The International Human Frontier Science Program Organization. We would like to thank U. McDermott for discussions and a critical reading of the manuscript.
This table shows clinical and pathology characteristics of patients and samples studied by massively parallel, paired-end sequencing.
This table shows somatically acquired genomic rearrangements in 13 patients with pancreatic cancer. All structural variants have been confirmed by PCR across the breakpoint, with bidirectional sequencing confirming the segments involved. Most have had the breakpoint annotated to base-pair resolution (‘Seq’ in the Evidence column): for the others, we provide a range of genomic positions encompassing the breakpoints (‘PCR across bkpt’). Length and sequence of either microhomology or non-templated sequence at the junction are shown.
This table shows the germline genomic rearrangements in 13 patients with pancreatic cancer. All structural variants have been confirmed by PCR across the breakpoint, with bidirectional sequencing confirming the segments involved. Length and sequence of either microhomology or non templated sequence at the junction are shown.
The table shows the genes involved at both breakpoints for each of the somatically acquired genomic rearrangements.
This table shows the presence or absence of each somatically acquired genomic rearrangement across the available metastasis and primary tumour samples for 10 patients (1 = present by PCR; 0 = absent by PCR).
About this article
Scientific Reports (2019)