The Clonal Evolution of Metastatic Colorectal Cancer

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2020 Jun 25

PMID 32577507

Citations 32

Authors

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

Soon will be listed here.

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.

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