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Sci Adv. 2020 Jun 10;6(24):eaay9691. doi: 10.1126/sciadv.aay9691. eCollection 2020 Jun.

The clonal evolution of metastatic colorectal cancer.

Science advances

Ha X Dang, Bradley A Krasnick, Brian S White, Julie G Grossman, Matthew S Strand, Jin Zhang, Christopher R Cabanski, Christopher A Miller, Robert S Fulton, S Peter Goedegebuure, Catrina C Fronick, Malachi Griffith, David E Larson, Brian D Goetz, Jason R Walker, William G Hawkins, Steven M Strasberg, David C Linehan, Kian H Lim, A Craig Lockhart, Elaine R Mardis, Richard K Wilson, Timothy J Ley, Christopher A Maher, Ryan C Fields

Affiliations

  1. Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
  2. McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
  3. The Alvin J. Siteman Comprehensive Cancer Center, Washington University in St. Louis, St. Louis, MO, USA.
  4. Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA.
  5. Barnes-Jewish Hospital, St. Louis, MO, USA.
  6. Sage Bionetworks, Seattle, WA, USA.
  7. Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, USA.
  8. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
  9. Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA.
  10. Department of Surgery and The Wilmot Cancer Institute, University of Rochester School of Medicine, Rochester, NY, USA.
  11. Division of Medical Oncology, Department of Medicine, The Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, USA.
  12. Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
  13. Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
  14. Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.

PMID: 32577507 PMCID: PMC7286679 DOI: 10.1126/sciadv.aay9691

Abstract

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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