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      mainEntity:
         headline:Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution
         description:Deep-genome and single-cell sequencing analyses of patient-derived breast cancer xenografts reveal extensive, dynamic and reproducible changes in intra-tumoral mutational clonal composition on engraftment and serial propagation. Xenograft transplantation of primary human cancer cells into mice provides valuable models in which to study mechanisms underlying tumorigenesis, drug response and resistance. This study demonstrates that clonal evolution resembling that seen in human tumours also occurs on engraftment and during subsequent passaging of breast tumours in immunodeficient mice. In addition, similar clonal expansion patterns emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. These findings suggest that patient-derived xenografts may be useful for studying patient-specific tumour characteristics such as the response to drugs tailored to specific genomic alterations. Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution1,2, underpinning important emergent features such as drug resistance and metastasis3,4,5,6,7. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours8,9,10. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.
         datePublished:2014-11-26T00:00:00Z
         dateModified:2014-11-26T00:00:00Z
         pageStart:422
         pageEnd:426
         sameAs:https://doi.org/10.1038/nature13952
         keywords:
            Breast cancer
            Cancer genomics
            Science
            Humanities and Social Sciences
            multidisciplinary
         image:
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         isPartOf:
            name:Nature
            issn:
               1476-4687
               0028-0836
            volumeNumber:518
            type:
               Periodical
               PublicationVolume
         publisher:
            name:Nature Publishing Group UK
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         author:
               name:Peter Eirew
               affiliation:
                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Adi Steif
               affiliation:
                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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               name:Jaswinder Khattra
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                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                        type:PostalAddress
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               type:Person
               name:Gavin Ha
               affiliation:
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                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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               name:Damian Yap
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                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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               name:Hossein Farahani
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                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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               name:Karen Gelmon
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                        name:Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada,
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               name:Stephen Chia
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                        name:Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada,
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                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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               name:Emma Laks
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                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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               name:Ali Bashashati
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                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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               name:Camila de Souza
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                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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               name:Celia Siu
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                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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               name:Tomo Osako
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                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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                     address:
                        name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
                        type:PostalAddress
                     type:Organization
                     name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK
                     address:
                        name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK,
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               type:Person
               name:Jose L. Sandoval
               affiliation:
                     name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
                     address:
                        name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
                        type:PostalAddress
                     type:Organization
                     name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK
                     address:
                        name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK,
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Teresa Algara
               affiliation:
                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Wendy Greenwood
               affiliation:
                     name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
                     address:
                        name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
                        type:PostalAddress
                     type:Organization
                     name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK
                     address:
                        name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK,
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                     type:Organization
               type:Person
               name:Kaston Leung
               affiliation:
                     name:Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
                     address:
                        name:Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
                     address:
                        name:Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada,
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Hongwei Cheng
               affiliation:
                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
                     address:
                        name:Vancouver General Hospital and Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada,
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               type:Person
               name:Hui Xue
               affiliation:
                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
                     address:
                        name:Vancouver General Hospital and Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada,
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Yuzhuo Wang
               affiliation:
                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
                     address:
                        name:Vancouver General Hospital and Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada,
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Dong Lin
               affiliation:
                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
                     address:
                        name:Vancouver General Hospital and Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada,
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Andrew J. Mungall
               affiliation:
                     name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
               type:Person
               name:Richard Moore
               affiliation:
                     name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada,
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               name:Yongjun Zhao
               affiliation:
                     name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada,
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               name:Julie Lorette
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                     address:
                        name:Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada,
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               name:Long Nguyen
               affiliation:
                     name:University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
                     address:
                        name:Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada
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                        name:Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
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               name:David Huntsman
               affiliation:
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                        type:PostalAddress
                     type:Organization
                     name:Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada
                     address:
                        name:Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada,
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               name:Connie J. Eaves
               affiliation:
                     name:University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
                     address:
                        name:Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada
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                        name:Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
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               name:Carl Hansen
               affiliation:
                     name:Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
                     address:
                        name:Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada,
                        type:PostalAddress
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                     name:University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
                     address:
                        name:Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada,
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               name:Marco A. Marra
               affiliation:
                     name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada
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                        name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada,
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               name:Carlos Caldas
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                        name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
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                     name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK
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               name:Sohrab P. Shah
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                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                        type:PostalAddress
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                     name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada
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                        name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada,
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               email:[email protected]
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               name:Samuel Aparicio
               affiliation:
                     name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                     address:
                        name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                        type:PostalAddress
                     type:Organization
                     name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada
                     address:
                        name:Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada,
                        type:PostalAddress
                     type:Organization
                     name:Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada
                     address:
                        name:Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada,
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ScholarlyArticle:
      headline:Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution
      description:Deep-genome and single-cell sequencing analyses of patient-derived breast cancer xenografts reveal extensive, dynamic and reproducible changes in intra-tumoral mutational clonal composition on engraftment and serial propagation. Xenograft transplantation of primary human cancer cells into mice provides valuable models in which to study mechanisms underlying tumorigenesis, drug response and resistance. This study demonstrates that clonal evolution resembling that seen in human tumours also occurs on engraftment and during subsequent passaging of breast tumours in immunodeficient mice. In addition, similar clonal expansion patterns emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. These findings suggest that patient-derived xenografts may be useful for studying patient-specific tumour characteristics such as the response to drugs tailored to specific genomic alterations. Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution1,2, underpinning important emergent features such as drug resistance and metastasis3,4,5,6,7. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours8,9,10. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.
      datePublished:2014-11-26T00:00:00Z
      dateModified:2014-11-26T00:00:00Z
      pageStart:422
      pageEnd:426
      sameAs:https://doi.org/10.1038/nature13952
      keywords:
         Breast cancer
         Cancer genomics
         Science
         Humanities and Social Sciences
         multidisciplinary
      image:
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      isPartOf:
         name:Nature
         issn:
            1476-4687
            0028-0836
         volumeNumber:518
         type:
            Periodical
            PublicationVolume
      publisher:
         name:Nature Publishing Group UK
         logo:
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            type:ImageObject
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      author:
            name:Peter Eirew
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Adi Steif
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
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            type:Person
            name:Jaswinder Khattra
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Gavin Ha
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
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            type:Person
            name:Damian Yap
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Hossein Farahani
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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            type:Person
            name:Karen Gelmon
            affiliation:
                  name:BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada
                  address:
                     name:Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada,
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            type:Person
            name:Stephen Chia
            affiliation:
                  name:BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada
                  address:
                     name:Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada,
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            type:Person
            name:Colin Mar
            affiliation:
                  name:BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada
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                     name:Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada,
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            type:Person
            name:Adrian Wan
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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            name:Emma Laks
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
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                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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            name:Justina Biele
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
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                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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            name:Karey Shumansky
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
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                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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            name:Jamie Rosner
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
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                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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            name:Andrew McPherson
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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            name:Cydney Nielsen
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
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                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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            name:Andrew J. L. Roth
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                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
                  type:Organization
            type:Person
            name:Calvin Lefebvre
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
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            type:Person
            name:Ali Bashashati
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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            name:Camila de Souza
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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            name:Celia Siu
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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            name:Radhouane Aniba
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
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                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
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            name:Jazmine Brimhall
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
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            name:Arusha Oloumi
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                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
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            type:Person
            name:Tomo Osako
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
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            type:Person
            name:Alejandra Bruna
            affiliation:
                  name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
                  address:
                     name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
                     type:PostalAddress
                  type:Organization
                  name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK
                  address:
                     name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK,
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            type:Person
            name:Jose L. Sandoval
            affiliation:
                  name:University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK
                  address:
                     name:Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK,
                     type:PostalAddress
                  type:Organization
                  name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK
                  address:
                     name:Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK,
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            type:Person
            name:Teresa Algara
            affiliation:
                  name:BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada
                  address:
                     name:Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada,
                     type:PostalAddress
                  type:Organization
                  name:University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada
                  address:
                     name:Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada,
                     type:PostalAddress
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            name:Wendy Greenwood
            affiliation:
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      name:Vancouver General Hospital and Department of Urologic Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada,
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