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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
We are grateful to the staff of the CTAG Molecular Pathology facility, members of the Library Technical Development, Library Construction, Sequencing and Bioinformatics teams at the Michael Smith Genome Sciences Centre for technical assistance with data generation, and S. Kalloger for assistance with sample collection. S.A. and S.P.S. are supported by Canada Research Chairs. P.E. is supported by a Michael Smith Foundation for Health Research (MSFHR) Fellowship. A.S. is supported by an NSERC CREATE scholarship through the graduate program in Genome Science and Technology at UBC. S.P.S. is a MSFHR scholar. We acknowledge long-term funding support provided by the BC Cancer Foundation. The S.A., S.P.S. and C.H. groups receive operating funds from the Canadian Breast Cancer Foundation, Canadian Cancer Society Research Institute, Terry Fox Research Institute, Genome Canada and Canadian Institutes for Health Research (CIHR). We thank S. Mullaly for critical reading of the manuscript.