Distant metastasis occurs late during the genetic evolution of pancreatic cancer

Journal name:
Nature
Volume:
467,
Pages:
1114–1117
Date published:
DOI:
doi:10.1038/nature09515
Received
Accepted
Published online

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.

At a glance

Figures

  1. Summary of somatic mutations in metastatic pancreatic cancers.
    Figure 1: Summary of somatic mutations in metastatic pancreatic cancers.

    a, Histopathology of primary infiltrating pancreatic cancer and metastatic pancreatic cancer to the peritoneum, liver and lung. In addition to infiltrating cancer cells in each lesion (arrows), non-neoplastic cell types are abundant. b, Total mutations representing parental clones (founder mutations), and clonal evolution (progressor mutations) within the primary carcinoma based on comparative lesion sequencing. Mutations common to all samples analysed were the most common category identified.

  2. Geographic mapping of metastatic clones within the primary carcinoma and proposed clonal evolution of Pa08.
    Figure 2: Geographic mapping of metastatic clones within the primary carcinoma and proposed clonal evolution of Pa08.

    a, Illustration of the pancreatic specimen removed from Pa08 at rapid autopsy, and the planes of sectioning of the specimen. b, Mapping of the parental clone and subclones identified by comparative lesion sequencing within serial sections of the infiltrating pancreatic carcinoma. Metastatic subclones giving rise to liver and lung metastases are non-randomly located within slice 3, indicated by blue circles. These clones are both geographically and genetically distinct from clones giving rise to peritoneal metastases in this same patient, indicated in green. c, Proposed clonal evolution based on the sequencing data. In this model, after development of the parental clone, ongoing clonal evolution continues within the primary carcinoma (yellow rectangle), and these subclones seed metastases in distant sites. *Two mutations were found in the TTN gene.

  3. Schema of the genetic evolution of pancreatic cancer.
    Figure 3: Schema of the genetic evolution of pancreatic cancer.

    Tumorigenesis begins with an initiating mutation in a normal cell that confers a selective growth advantage. Successive waves of clonal expansion occur in association with the acquisition of additional mutations, corresponding to the progression model of pancreatic intraepithelial neoplasia (PanIN) and time T1. One founder cell within a PanIN lesion will seed the parental clone and hence initiate an infiltrating carcinoma (end of T1 and beginning of T2). Eventually, the cell that will give rise to the index lesion will appear (end of T2 and beginning of T3). Unfortunately, most patients are not diagnosed until well into time interval T3 when cells of these metastatic subclones have already escaped the pancreas and started to grow within distant organs. The average time for intervals T1, T2 and T3 for all seven patients is indicated in the parentheses at left (see also Supplementary Table 6).

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Author information

  1. These authors contributed equally to this work.

    • Shinichi Yachida &
    • Siân Jones

Affiliations

  1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA

    • Shinichi Yachida,
    • Baojin Fu,
    • Mihoko Kamiyama,
    • Ralph H. Hruban,
    • James R. Eshleman &
    • Christine A. Iacobuzio-Donahue
  2. The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21231, USA

    • Siân Jones,
    • Rebecca Leary,
    • Victor E. Velculescu,
    • Kenneth W. Kinzler &
    • Bert Vogelstein
  3. Program for Evolutionary Dynamics, Department of Mathematics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Ivana Bozic,
    • Tibor Antal &
    • Martin A. Nowak
  4. School of Mathematics, University of Edinburgh, Edinburgh EH9 3JZ, UK

    • Tibor Antal
  5. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA

    • Ralph H. Hruban &
    • Christine A. Iacobuzio-Donahue
  6. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA

    • Christine A. Iacobuzio-Donahue

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.

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The authors declare no competing financial interests.

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Supplementary information

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  1. Supplementary Information (679K)

    This file contains a Supplementary Discussion, additional references, Supplementary Figures 1-8 with legends and Supplementary Tables 1-6.

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