Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors

Abstract

We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 and TP53 (54.5%), followed by FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia, BilIN), but a substantial proportion was subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. Combined analysis with metastatic tumors (n=11) identified branching evolution in 9 patients (81.8%). Of these, 8 patients (88.9%) had a total of 11 subclones expanded at least 7-fold during metastasis. These subclones harbored putative metastasis-driving mutations in cancer-related genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, 6 mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.

Data availability

The raw sequence data underlying this manuscript are available as fastq files at the NCBI SRA database under the BioProject number PRJNA821382.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Minsu Kang

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6491-2277
  2. Hee Young Na

    Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  3. Soomin Ahn

    Department of Pathology and Translational Medicine, Samsung Medical Center, Seoul, Republic of Korea
    For correspondence
    suminy317@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
  4. Ji-Won Kim

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    For correspondence
    jiwonkim@snubh.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6426-9074
  5. Sejoon Lee

    Center for Precision Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Soyeon Ahn

    Medical Research Collaboration Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  7. Ju Hyun Lee

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  8. Jeonghwan Youk

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Haesook T Kim

    Department of Data Science, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kui-Jin Kim

    Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  11. Koung Jin Suh

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  12. Jun Suh Lee

    Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  13. Se Hyun Kim

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2292-906X
  14. Jin Won Kim

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  15. Yu Jung Kim

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  16. Keun-Wook Lee

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  17. Yoo-Seok Yoon

    Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  18. Jee Hyun Kim

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  19. Jin-Haeng Chung

    Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  20. Ho-Seong Han

    Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  21. Jong Seok Lee

    Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.

Funding

Seoul National University Bundang Hospital Research Fund (No. 16-2021-001)

  • Ji-Won Kim

Small Grant for Exploratory Reserach (NRF-2018R1D1A1A02086240)

  • Ji-Won Kim

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Samra Turajlic, The Francis Crick Institute, United Kingdom

Ethics

Human subjects: This study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Seoul National University Bundang Hospital (Number: B-1902/522-303). Informed consent was waived because of the retrospective and anonymous nature of the study.

Version history

  1. Received: March 14, 2022
  2. Preprint posted: April 1, 2022 (view preprint)
  3. Accepted: December 6, 2022
  4. Accepted Manuscript published: December 8, 2022 (version 1)
  5. Accepted Manuscript updated: December 16, 2022 (version 2)
  6. Version of Record published: December 21, 2022 (version 3)

Copyright

© 2022, Kang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Minsu Kang
  2. Hee Young Na
  3. Soomin Ahn
  4. Ji-Won Kim
  5. Sejoon Lee
  6. Soyeon Ahn
  7. Ju Hyun Lee
  8. Jeonghwan Youk
  9. Haesook T Kim
  10. Kui-Jin Kim
  11. Koung Jin Suh
  12. Jun Suh Lee
  13. Se Hyun Kim
  14. Jin Won Kim
  15. Yu Jung Kim
  16. Keun-Wook Lee
  17. Yoo-Seok Yoon
  18. Jee Hyun Kim
  19. Jin-Haeng Chung
  20. Ho-Seong Han
  21. Jong Seok Lee
(2022)
Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors
eLife 11:e78636.
https://doi.org/10.7554/eLife.78636

Share this article

https://doi.org/10.7554/eLife.78636

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