Unstable Genome and Transcriptome Dynamics during Tumor Metastasis Contribute to Therapeutic Heterogeneity in Colorectal Cancers.

Document Type

Article

Publication Date

5-2019

Keywords

JGM

JAX Source

Clin Cancer Res 2019 May; 25(9):2821-2834

Volume

25

Issue

9

First Page

2821

Last Page

2834

ISSN

1078-0432

PMID

30670495

DOI

https://doi.org/10.1158/1078-0432.CCR-18-3460

Grant

CA034196, Ewha Womans University Research Grant

Abstract

PURPOSE: Genomic and transcriptomic alterations during metastasis are considered to affect clinical outcome of colorectal cancers, but detailed clinical implications of metastatic alterations are not fully uncovered. We aimed to investigate the effect of metastatic evolution on

EXPERIMENTAL DESIGN: We developed and analyzed patient-derived xenograft (PDX) models from 35 patients with colorectal cancer including 5 patients with multiple organ metastases (MOMs). We performed whole-exome, DNA methylation, and RNA sequencing for patient and PDX tumors. With samples from patients with MOMs, we conducted phylogenetic and subclonal analysis and

RESULTS: Phylogenetic analysis using mutation, expression, and DNA methylation data in patients with MOMs showed that mutational alterations were closely connected with transcriptomic and epigenomic changes during the tumor evolution. Subclonal analysis revealed that initial primary tumors with larger number of subclones exhibited more dynamic changes in subclonal architecture according to metastasis, and loco-regional and distant metastases occurred in a parallel or independent fashion. The PDX models from MOMs demonstrated therapeutic heterogeneity for targeted treatment, due to subclonal acquisition of additional mutations or transcriptomic activation of bypass signaling pathway during tumor evolution.

CONCLUSIONS: This study demonstrated

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