The clonal evolution of metastatic colorectal cancer

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 LockhartElaine R. Mardis, Richard K. Wilson, Timothy J. Ley, Christopher A. Maher, Ryan C. Fields

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbereaay9691
JournalScience Advances
Volume6
Issue number24
DOIs
StatePublished - Jun 2020

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'The clonal evolution of metastatic colorectal cancer'. Together they form a unique fingerprint.

Cite this