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Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models

Author

Listed:
  • Robert E. Hynds

    (University College London Cancer Institute
    The Francis Crick Institute
    Great Ormond Street University College London Institute of Child Health)

  • Ariana Huebner

    (University College London Cancer Institute
    The Francis Crick Institute
    University College London Cancer Institute)

  • David R. Pearce

    (University College London Cancer Institute
    The Francis Crick Institute)

  • Mark S. Hill

    (The Francis Crick Institute)

  • Ayse U. Akarca

    (University College London Hospitals)

  • David A. Moore

    (University College London Cancer Institute
    The Francis Crick Institute
    University College London Hospitals)

  • Sophia Ward

    (University College London Cancer Institute
    The Francis Crick Institute
    The Francis Crick Institute)

  • Kate H. C. Gowers

    (University College London)

  • Takahiro Karasaki

    (University College London Cancer Institute
    The Francis Crick Institute
    University College London Cancer Institute)

  • Maise Al Bakir

    (University College London Cancer Institute
    The Francis Crick Institute)

  • Gareth A. Wilson

    (The Francis Crick Institute)

  • Oriol Pich

    (University College London Cancer Institute
    The Francis Crick Institute)

  • Carlos Martínez-Ruiz

    (University College London Cancer Institute
    University College London Cancer Institute)

  • A. S. Md Mukarram Hossain

    (University of Manchester
    University of Manchester)

  • Simon P. Pearce

    (University of Manchester
    University of Manchester)

  • Monica Sivakumar

    (University College London Cancer Institute
    University College London Hospitals)

  • Assma Aissa

    (University College London Cancer Institute)

  • Eva Grönroos

    (The Francis Crick Institute)

  • Deepak Chandrasekharan

    (University College London)

  • Krishna K. Kolluri

    (University College London)

  • Rebecca Towns

    (University College London)

  • Kaiwen Wang

    (University of Leeds)

  • Daniel E. Cook

    (The Francis Crick Institute)

  • Leticia Bosshard-Carter

    (University College London Cancer Institute
    University College London)

  • Cristina Naceur-Lombardelli

    (University College London Cancer Institute)

  • Andrew J. Rowan

    (The Francis Crick Institute)

  • Selvaraju Veeriah

    (University College London Cancer Institute)

  • Kevin Litchfield

    (University College London Cancer Institute
    University College London Cancer Institute)

  • Philip A. J. Crosbie

    (University of Manchester
    University of Manchester)

  • Caroline Dive

    (University of Manchester
    University of Manchester)

  • Sergio A. Quezada

    (University College London Cancer Institute
    University College London Cancer Institute)

  • Sam M. Janes

    (University College London)

  • Mariam Jamal-Hanjani

    (University College London Cancer Institute
    University College London Cancer Institute
    University College London Hospitals)

  • Teresa Marafioti

    (University College London Hospitals)

  • Nicholas McGranahan

    (University College London Cancer Institute
    University College London Cancer Institute)

  • Charles Swanton

    (University College London Cancer Institute
    The Francis Crick Institute
    University College London Hospitals)

Abstract

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

Suggested Citation

  • Robert E. Hynds & Ariana Huebner & David R. Pearce & Mark S. Hill & Ayse U. Akarca & David A. Moore & Sophia Ward & Kate H. C. Gowers & Takahiro Karasaki & Maise Al Bakir & Gareth A. Wilson & Oriol Pi, 2024. "Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47547-3
    DOI: 10.1038/s41467-024-47547-3
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    References listed on IDEAS

    as
    1. Peter Eirew & Adi Steif & Jaswinder Khattra & Gavin Ha & Damian Yap & Hossein Farahani & Karen Gelmon & Stephen Chia & Colin Mar & Adrian Wan & Emma Laks & Justina Biele & Karey Shumansky & Jamie Rosn, 2015. "Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution," Nature, Nature, vol. 518(7539), pages 422-426, February.
    Full references (including those not matched with items on IDEAS)

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