The clonal evolution of metastatic colorectal cancer

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...

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Published inScience advances Vol. 6; no. 24; p. eaay9691
Main Authors Dang, Ha X, Krasnick, Bradley A, White, Brian S, Grossman, Julie G, Strand, Matthew S, Zhang, Jin, Cabanski, Christopher R, Miller, Christopher A, Fulton, Robert S, Goedegebuure, S Peter, Fronick, Catrina C, Griffith, Malachi, Larson, David E, Goetz, Brian D, Walker, Jason R, Hawkins, William G, Strasberg, Steven M, Linehan, David C, Lim, Kian H, Lockhart, A Craig, Mardis, Elaine R, Wilson, Richard K, Ley, Timothy J, Maher, Christopher A, Fields, Ryan C
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 01.06.2020
Subjects
Animals
Cancer
Cell Biology
Clonal Evolution - genetics
Colonic Neoplasms - genetics
Disease Models, Animal
Exome - genetics
Genomics
Humans
Neoplasm Metastasis
SciAdv r-articles
Whole Exome Sequencing
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Summary: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.
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These authors contributed equally to this work.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aay9691