The patterns and dynamics of genomic instability in metastatic pancreatic cancer

Peter J. Campbell, Shinichi Yachida, Laura J. Mudie, Philip J. Stephens, Erin D. Pleasance, Lucy A. Stebbings, Laura A. Morsberger, Calli Latimer, Stuart McLaren, Meng-Lay Lin, David J. McBride, Ignacio Varela, Serena A. Nik-Zainal, Catherine Leroy, Mingming Jia, Andrew Menzies, Adam P. Butler, Jon W. Teague, Constance A. Griffin, John Burton, Harold Swerdlow, Michael A. Quail, Michael R. Stratton, Christine Iacobuzio-Donahue () and P. Andrew Futreal ()
Additional contact information
Peter J. Campbell: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Shinichi Yachida: Johns Hopkins Medical Institutions
Laura J. Mudie: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Philip J. Stephens: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Erin D. Pleasance: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Lucy A. Stebbings: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Laura A. Morsberger: Johns Hopkins Medical Institutions
Calli Latimer: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Stuart McLaren: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Meng-Lay Lin: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
David J. McBride: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Ignacio Varela: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Serena A. Nik-Zainal: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Catherine Leroy: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Mingming Jia: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Andrew Menzies: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Adam P. Butler: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Jon W. Teague: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Constance A. Griffin: Johns Hopkins Medical Institutions
John Burton: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Harold Swerdlow: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Michael A. Quail: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Michael R. Stratton: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Christine Iacobuzio-Donahue: Johns Hopkins Medical Institutions
P. Andrew Futreal: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK

Nature, 2010, vol. 467, issue 7319, 1109-1113

Abstract: A timeline for pancreatic cancer Christine Iacobuzio-Donahue and colleagues use whole-genome exome sequencing to analyse primary pancreatic cancers and one or more metastases from the same patients, and find that tumours are composed of distinct subclones. The authors also determine the evolutionary maps by which metastatic cancer clones have evolved within the primary tumour, and estimate the timescales of tumour progression. On the basis of these data, they estimate a mean period of 11.8 years between the initiation of pancreatic tumorigenesis and the formation of the parental, non-metastatic tumour, and a further 6.8 years for the index metastasis clone to arise. These data point to a potentially large window of opportunity during which it might be possible to detect the cancer in a relatively early form. Peter Campbell and colleagues use next-generation sequencing to detect chromosomal rearrangements in 13 patients with pancreatic cancer. The results reveal considerable inter-patient heterogeneity and indicate ongoing genomic instability and evolution during the development of metastases. But for most of the patients studied, more than half of the genetic rearrangements found were present in all metastases and the primary tumour, making them potential targets for therapeutic intervention at early and late stages of the disease.

Date: 2010
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DOI: 10.1038/nature09460

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