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Unstable Genome and Transcriptome Dynamics during Tumor Metastasis Contribute to Therapeutic Heterogeneity in Colorectal Cancers.
Cho, Sung-Yup; Chae, Jeesoo; Na, Deukchae; Kang, Wonyoung; Lee, Ahra; Min, Seoyeon; Kang, Jinjoo; Choi, Boram; Lee, Jieun; Sung, Chang Ohk; Chuang, Jeffrey H; Lee, Charles; Lee, Won-Suk; Park, Hansoo; Kim, Jong-Il.
Affiliation
  • Cho SY; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
  • Chae J; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
  • Na D; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
  • Kang W; Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Korea.
  • Lee A; Department of Life Science, Ewha Womans University, Seoul, Korea.
  • Min S; Department of Life Science, Ewha Womans University, Seoul, Korea.
  • Kang J; Department of Life Science, Ewha Womans University, Seoul, Korea.
  • Choi B; Department of Life Science, Ewha Womans University, Seoul, Korea.
  • Lee J; Department of Life Science, Ewha Womans University, Seoul, Korea.
  • Sung CO; Department of Life Science, Ewha Womans University, Seoul, Korea.
  • Chuang JH; Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Lee C; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
  • Lee WS; Department of Life Science, Ewha Womans University, Seoul, Korea.
  • Park H; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
  • Kim JI; Department of Surgery, Gil Medical Center, Gachon University, Incheon, Korea. jongil@snu.ac.kr lws@gilhospital.com hspark27@gist.ac.kr.
Clin Cancer Res ; 25(9): 2821-2834, 2019 05 01.
Article in En | MEDLINE | ID: mdl-30670495
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 in vivo treatment outcome, and identify genomic and transcriptomic alterations associated with drug responsiveness. 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 in vivo drug efficacy test on the corresponding PDX models.

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 in vivo therapeutic heterogeneity of colorectal cancers using PDX models, and suggests that acquired subclonal alterations in mutations or gene expression profiles during tumor metastatic processes can be associated with the development of drug resistance and therapeutic heterogeneity of colorectal cancers.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colorectal Neoplasms / Biomarkers, Tumor / Genome, Human / Genetic Heterogeneity / Transcriptome / Mutation / Antineoplastic Agents Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Clin Cancer Res Journal subject: NEOPLASIAS Year: 2019 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colorectal Neoplasms / Biomarkers, Tumor / Genome, Human / Genetic Heterogeneity / Transcriptome / Mutation / Antineoplastic Agents Type of study: Prognostic_studies Limits: Animals / Female / Humans Language: En Journal: Clin Cancer Res Journal subject: NEOPLASIAS Year: 2019 Document type: Article