ABSTRACT Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated1,2, is the most common cause of death in cancer patients. This

is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy3. Whether the

dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not

known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that

performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required

for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer

progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease. Access through your institution Buy or subscribe This is a preview of

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CONSTRAINS THE GROWTH AND METABOLISM OF METASTASES Article 19 August 2024 EVOLUTIONARY PATHS TOWARDS METASTASIS Article 22 April 2025 GENOMIC CONTROL OF METASTASIS Article Open access 04

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human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. _J. Natl. Cancer Inst._ 98, 316–325 (2006) Article  Google Scholar  Download references ACKNOWLEDGEMENTS This

work was supported by National Institutes of Health grants CA106610 (C.A.I.-D.), CA62924 (C.A.I.-D., M.A.N.), CA43460 (B.V.), CA57345 (K.W.K. and V.E.V.), CA121113 (V.E.V. and K.W.K.),

GM078986 (M.A.N.), the Bill and Melinda Gates Foundation Grand Challenges Grant 37874, the Uehara Memorial Foundation (S.Y.), the AACR-Barletta Foundation (C.A.I.-D.), the John Templeton

Foundation, Pilot Funding from the Sol Goldman Pancreatic Cancer Research Center, the Michael Rolfe Pancreatic Cancer Foundation, the George Rubis Endowment for Pancreatic Cancer Research,

the Joseph C. Monastra Foundation for Pancreatic Cancer Research, the Alfredo Scatena Memorial Fund, the Virginia and the D.K. Ludwig Fund for Cancer Research, The Joint Program in

Mathematical Biology and J. Epstein. We would like to acknowledge T. C. Cornish, C. Henderson, N. Omura and S.-M. Hong for their technical assistance in selected aspects of this work. AUTHOR

INFORMATION Author notes * Shinichi Yachida and Siân Jones: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Pathology, The Sol Goldman Pancreatic

Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, 21231, Maryland, USA Shinichi Yachida, Baojin Fu, Mihoko Kamiyama, Ralph H. Hruban, James R. Eshleman & Christine

A. Iacobuzio-Donahue * The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, 21231, Maryland,

USA Siân Jones, Rebecca Leary, Victor E. Velculescu, Kenneth W. Kinzler & Bert Vogelstein * Department of Mathematics, Department of Organismic and Evolutionary Biology, Program for

Evolutionary Dynamics, Harvard University, Cambridge, 02138, Massachusetts, USA Ivana Bozic, Tibor Antal & Martin A. Nowak * School of Mathematics, University of Edinburgh, Edinburgh EH9

3JZ, UK Tibor Antal * Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, 21231, Maryland, USA Ralph H. Hruban & 

Christine A. Iacobuzio-Donahue * Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, 21231, Maryland, USA Christine A.

Iacobuzio-Donahue Authors * Shinichi Yachida View author publications You can also search for this author inPubMed Google Scholar * Siân Jones View author publications You can also search

for this author inPubMed Google Scholar * Ivana Bozic View author publications You can also search for this author inPubMed Google Scholar * Tibor Antal View author publications You can also

search for this author inPubMed Google Scholar * Rebecca Leary View author publications You can also search for this author inPubMed Google Scholar * Baojin Fu View author publications You

can also search for this author inPubMed Google Scholar * Mihoko Kamiyama View author publications You can also search for this author inPubMed Google Scholar * Ralph H. Hruban View author

publications You can also search for this author inPubMed Google Scholar * James R. Eshleman View author publications You can also search for this author inPubMed Google Scholar * Martin A.

Nowak View author publications You can also search for this author inPubMed Google Scholar * Victor E. Velculescu View author publications You can also search for this author inPubMed Google

Scholar * Kenneth W. Kinzler View author publications You can also search for this author inPubMed Google Scholar * Bert Vogelstein View author publications You can also search for this

author inPubMed Google Scholar * Christine A. Iacobuzio-Donahue View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Sample collection and

processing was performed by C.A.I.-D., S.Y., B.F. and M.K. Microdissection, DNA extractions and whole genome amplification reactions were performed by S.Y. Sequencing was performed by S.J.

Copy number analyses were performed by R.L. Computational models and estimates of clonal evolution were performed by I.B., T.A. and M.A.N.; C.A.I.-D., S.Y., S.J., R.H.H., J.R.E., M.A.N.,

I.B., T.A., V.E.V., K.W.K. and B.V. directed the research. C.A.I.-D., B.V., S.Y., I.B. and T.A. wrote the manuscript, which all authors have approved. CORRESPONDING AUTHOR Correspondence to

Christine A. Iacobuzio-Donahue. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file

contains a Supplementary Discussion, additional references, Supplementary Figures 1-8 with legends and Supplementary Tables 1-6. (PDF 679 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1

POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Yachida, S., Jones, S., Bozic, I. _et al._

Distant metastasis occurs late during the genetic evolution of pancreatic cancer. _Nature_ 467, 1114–1117 (2010). https://doi.org/10.1038/nature09515 Download citation * Received: 11 May

2010 * Accepted: 15 September 2010 * Published: 27 October 2010 * Issue Date: 28 October 2010 * DOI: https://doi.org/10.1038/nature09515 SHARE THIS ARTICLE Anyone you share the following

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