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         headline:Distant metastasis occurs late during the genetic evolution of pancreatic cancer
         description: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. Here, whole-genome sequencing has been used to analyse primary pancreatic tumours and one or more metastases from the same patients. The findings show that tumours are composed of several geographically distinct subclones, and allow maps to be produced showing how metastatic cancer clones evolve within the primary tumour. Moreover, a quantitative analysis of the timing of the genetic evolution of pancreatic cancer has been performed. 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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      headline:Distant metastasis occurs late during the genetic evolution of pancreatic cancer
      description: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. Here, whole-genome sequencing has been used to analyse primary pancreatic tumours and one or more metastases from the same patients. The findings show that tumours are composed of several geographically distinct subclones, and allow maps to be produced showing how metastatic cancer clones evolve within the primary tumour. Moreover, a quantitative analysis of the timing of the genetic evolution of pancreatic cancer has been performed. 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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      name:Shinichi Yachida
      affiliation:
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Siân Jones
      affiliation:
            name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center
            address:
               name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Ivana Bozic
      affiliation:
            name:Program for Evolutionary Dynamics, Harvard University
            address:
               name:Department of Mathematics, Department of Organismic and Evolutionary Biology, Program for Evolutionary Dynamics, Harvard University, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Tibor Antal
      affiliation:
            name:Program for Evolutionary Dynamics, Harvard University
            address:
               name:Department of Mathematics, Department of Organismic and Evolutionary Biology, Program for Evolutionary Dynamics, Harvard University, Cambridge, USA
               type:PostalAddress
            type:Organization
            name:School of Mathematics, University of Edinburgh
            address:
               name:School of Mathematics, University of Edinburgh, Edinburgh EH9 3JZ, UK
               type:PostalAddress
            type:Organization
      name:Rebecca Leary
      affiliation:
            name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center
            address:
               name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Baojin Fu
      affiliation:
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Mihoko Kamiyama
      affiliation:
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Ralph H. Hruban
      affiliation:
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:James R. Eshleman
      affiliation:
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Martin A. Nowak
      affiliation:
            name:Program for Evolutionary Dynamics, Harvard University
            address:
               name:Department of Mathematics, Department of Organismic and Evolutionary Biology, Program for Evolutionary Dynamics, Harvard University, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Victor E. Velculescu
      affiliation:
            name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center
            address:
               name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Kenneth W. Kinzler
      affiliation:
            name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center
            address:
               name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Bert Vogelstein
      affiliation:
            name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center
            address:
               name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
               type:PostalAddress
            type:Organization
      name:Christine A. Iacobuzio-Donahue
      affiliation:
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
            name:The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions
            address:
               name:Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
      name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
      name:Department of Mathematics, Department of Organismic and Evolutionary Biology, Program for Evolutionary Dynamics, Harvard University, Cambridge, USA
      name:Department of Mathematics, Department of Organismic and Evolutionary Biology, Program for Evolutionary Dynamics, Harvard University, Cambridge, USA
      name:School of Mathematics, University of Edinburgh, Edinburgh EH9 3JZ, UK
      name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
      name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Mathematics, Department of Organismic and Evolutionary Biology, Program for Evolutionary Dynamics, Harvard University, Cambridge, USA
      name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
      name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
      name:The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, USA
      name:Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
      name:Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, USA
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