Distant metastasis occurs late during the genetic evolution of pancreatic cancer

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

clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic

clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was

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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ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS LYMPH NODE METASTASES DEVELOP

THROUGH A WIDER EVOLUTIONARY BOTTLENECK THAN DISTANT METASTASES Article 25 May 2020 CANCER TISSUE OF ORIGIN CONSTRAINS THE GROWTH AND METABOLISM OF METASTASES Article 19 August 2024

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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

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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

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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

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