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DNA-based copy number analysis confirms genomic evolution of PDX models

Anna C. H. Hoge, Michal Getz, Rameen Beroukhim, Todd R. Golub, Gavin Ha, View ORCID ProfileUri Ben-David
doi: https://doi.org/10.1101/2021.01.15.426865
Anna C. H. Hoge
1Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Michal Getz
2Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Rameen Beroukhim
3Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
4Dana-Farber Cancer Institute, Boston, Massachusetts, USA
5Harvard Medical School, Boston, Massachusetts, USA
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Todd R. Golub
3Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
4Dana-Farber Cancer Institute, Boston, Massachusetts, USA
5Harvard Medical School, Boston, Massachusetts, USA
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Gavin Ha
1Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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  • For correspondence: gha@fredhutch.org ubendavid@tauex.tau.ac.il
Uri Ben-David
2Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • ORCID record for Uri Ben-David
  • For correspondence: gha@fredhutch.org ubendavid@tauex.tau.ac.il
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Abstract

We previously reported the genomic evolution of the copy number (CN) landscapes of patient-derived xenografts (PDXs) during their engraftment and passaging1. Woo et al. argue that the CN profiles of PDXs are highly conserved, and that the main conclusions of our paper are invalid due to our use of expression-based CN profiles2. Here, we reassess genomic evolution of PDXs using the DNA-based CN profiles reported by Woo et al. We find that the degree of genomic evolution in the DNA-based dataset of Woo et al. is similar to that which we had previously reported. While the overall Pearson’s correlation of CN profiles between primary tumors (PTs) and their derived PDXs is high (as reported in our original paper as well), a median of ~10% of the genome is differentially altered between PTs and PDXs across cohorts (range, 0% to 73% across all models). In 24% of the matched PT-PDX samples, over a quarter of the genome is differentially affected by CN alterations. Moreover, in matched analyses of PTs and their derived PDXs at multiple passages, later-passage PDXs are significantly less similar to their parental PTs than earlier-passage PDXs, indicative of genomic divergence. We conclude that genomic evolution of PDX models during model generation and propagation should not be dismissed, and that the phenotypic consequences of this evolution ought to be assessed in order to optimize the application of these valuable cancer models.

Competing Interest Statement

T.R.G. is a consultant to GlaxoSmithKline and is a founder of Sherlock Biosciences. R.B. own shares in Ampressa and receives grant funding from Novartis. The other authors declare no competing interests.

Footnotes

  • ↵# Equally-contributing first authors

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 17, 2021.
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DNA-based copy number analysis confirms genomic evolution of PDX models
Anna C. H. Hoge, Michal Getz, Rameen Beroukhim, Todd R. Golub, Gavin Ha, Uri Ben-David
bioRxiv 2021.01.15.426865; doi: https://doi.org/10.1101/2021.01.15.426865
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DNA-based copy number analysis confirms genomic evolution of PDX models
Anna C. H. Hoge, Michal Getz, Rameen Beroukhim, Todd R. Golub, Gavin Ha, Uri Ben-David
bioRxiv 2021.01.15.426865; doi: https://doi.org/10.1101/2021.01.15.426865

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