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Distant metastasis occurs late during the genetic evolution of pancreatic cancer


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.

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Figure 1: Summary of somatic mutations in metastatic pancreatic cancers.
Figure 2: Geographic mapping of metastatic clones within the primary carcinoma and proposed clonal evolution of Pa08.
Figure 3: Schema of the genetic evolution of pancreatic cancer.

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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.

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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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Correspondence to Christine A. Iacobuzio-Donahue.

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The authors declare no competing financial interests.

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Yachida, S., Jones, S., Bozic, I. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

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