title: Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution.
abstract: Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. 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 tumours. 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.
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Eirew
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Adi
authors.initials: A
authors.lastname: Steif
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Jaswinder
authors.initials: J
authors.lastname: Khattra
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Gavin
authors.initials: G
authors.lastname: Ha
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Damian
authors.initials: D
authors.lastname: Yap
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Hossein
authors.initials: H
authors.lastname: Farahani
authors.affiliation: Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Gelmon
authors.affiliation: Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chia
authors.affiliation: Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.
authors.forename: Colin
authors.initials: C
authors.lastname: Mar
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wan
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Laks
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Justina
authors.initials: J
authors.lastname: Biele
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Karey
authors.initials: K
authors.lastname: Shumansky
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rosner
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: McPherson
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Cydney
authors.initials: C
authors.lastname: Nielsen
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Andrew J L
authors.initials: AJ
authors.lastname: Roth
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Calvin
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Bashashati
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Camila
authors.initials: C
authors.lastname: de Souza
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Celia
authors.initials: C
authors.lastname: Siu
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Radhouane
authors.initials: R
authors.lastname: Aniba
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Jazmine
authors.initials: J
authors.lastname: Brimhall
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Arusha
authors.initials: A
authors.lastname: Oloumi
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Tomo
authors.initials: T
authors.lastname: Osako
authors.affiliation: 1] Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK [2] Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Bruna
authors.affiliation: 1] Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK [2] Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Sandoval
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Teresa
authors.initials: T
authors.lastname: Algara
authors.affiliation: 1] Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK [2] Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Greenwood
authors.affiliation: 1] Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada [2] Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Kaston
authors.initials: K
authors.lastname: Leung
authors.affiliation: 1] Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.affiliation: 1] Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.affiliation: 1] Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Dong
authors.initials: D
authors.lastname: Lin
authors.affiliation: Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Andrew J
authors.initials: AJ
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authors.affiliation: Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.affiliation: Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Yongjun
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authors.affiliation: Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.
authors.forename: Julie
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authors.affiliation: 1] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada [2] Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Long
authors.initials: L
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authors.affiliation: 1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [2] Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.
authors.forename: David
authors.initials: D
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authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
authors.affiliation: 1] Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada [2] Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Carl
authors.initials: C
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authors.affiliation: Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Marco A
authors.initials: MA
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authors.affiliation: 1] Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK [2] Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [3] Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [3] Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada [4] Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.
authors.forename: Samuel
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authors.lastname: Aparicio
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000556:secondary; D002999:Clone Cells / Q000378:metabolism* / Q000473:pathology*; D004252:DNA Mutational Analysis; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D059010:Single-Cell Analysis; D013997:Time Factors; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays / Q000379:methods