Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of preexisting minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Notably, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have major implications for PDX-based modeling of human cancer.

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We thank L. Franke for assistance with functional genomic mRNA profiling; A. Bass, K. Ligon, A.J. Aguirre and J. Lorch for providing the clinical samples for cell line derivation; A. Tubelli for assistance with figure preparation; M. Meyerson, A.J. Cherniack, A. Taylor, A. Pearson and Z. Tothova for helpful discussions; and W.J. Gibson for copy number data. U.B.-D. is supported by a Human Frontiers Science Program postdoctoral fellowship, R.B. received support from the US National Institutes of Health (R01 CA188228) and the Gray Matters Brain Cancer Foundation, and T.R.G. received support from the Howard Hughes Medical Institute.

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Author notes

    • Rameen Beroukhim
    •  & Todd R Golub

    These authors jointly directed this work.


  1. Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Uri Ben-David
    • , Gavin Ha
    • , Yuen-Yi Tseng
    • , Noah F Greenwald
    • , Coyin Oh
    • , Juliann Shih
    • , James M McFarland
    • , Bang Wong
    • , Jesse S Boehm
    • , Rameen Beroukhim
    •  & Todd R Golub
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Gavin Ha
    •  & Juliann Shih
  3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Noah F Greenwald
    •  & Rameen Beroukhim
  4. Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Noah F Greenwald
  5. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Rameen Beroukhim
  6. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Rameen Beroukhim
  7. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Todd R Golub
  8. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

    • Todd R Golub
  9. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Todd R Golub


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U.B.-D. conceived the project, collected the data and carried out the analyses. G.H., N.F.G. and J.M.M. assisted with computational analyses. Y.-Y.T. and J.S.B. provided cell line data. C.O. assisted with the copy number analysis of cell lines. B.W. assisted with figure design and preparation. J.S. assisted with the copy number analysis of TCGA samples. R.B. and T.R.G. directed the project. U.B.-D., R.B. and T.R.G. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Rameen Beroukhim or Todd R Golub.

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    Supplementary Data 1

    CNA profiles of PDX samples.

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    Supplementary Data 2

    Model-acquired CNAs in PDX samples.

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    Supplementary Data 3

    CNA profiles of CLDX samples.

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    Supplementary Data 4

    Model-acquired CNAs in CLDX samples.

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