title: The patterns and dynamics of genomic instability in metastatic pancreatic cancer.
abstract: 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 mutations, 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 tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness 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 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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Mudie
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Erin D
authors.initials: ED
authors.lastname: Pleasance
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Stebbings
authors.forename: Laura A
authors.initials: LA
authors.lastname: Morsberger
authors.forename: Calli
authors.initials: C
authors.lastname: Latimer
authors.forename: Stuart
authors.initials: S
authors.lastname: McLaren
authors.forename: Meng-Lay
authors.initials: ML
authors.lastname: Lin
authors.forename: David J
authors.initials: DJ
authors.lastname: McBride
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.forename: Serena A
authors.initials: SA
authors.lastname: Nik-Zainal
authors.forename: Catherine
authors.initials: C
authors.lastname: Leroy
authors.forename: Mingming
authors.initials: M
authors.lastname: Jia
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.forename: Adam P
authors.initials: AP
authors.lastname: Butler
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.forename: Constance A
authors.initials: CA
authors.lastname: Griffin
authors.forename: John
authors.initials: J
authors.lastname: Burton
authors.forename: Harold
authors.initials: H
authors.lastname: Swerdlow
authors.forename: Michael A
authors.initials: MA
authors.lastname: Quail
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019143:Evolution, Molecular; D052138:Genes, Neoplasm / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D016296:Mutagenesis / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D016615:Telomere / Q000235:genetics / Q000473:pathology