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Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma

  • Author Footnotes
    † These authors contributed equally to this work.
    Liang-Qing Dong
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Author Footnotes
    † These authors contributed equally to this work.
    Yang Shi
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
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  • Author Footnotes
    † These authors contributed equally to this work.
    Li-Jie Ma
    Footnotes
    † These authors contributed equally to this work.
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Liu-Xiao Yang
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Xiao-Ying Wang
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Shu Zhang
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Zhi-Chao Wang
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Meng Duan
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Zhao Zhang
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Long-Zi Liu
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Bo-Hao Zheng
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Zhen-Bin Ding
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Ai-Wu Ke
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China
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  • Da-Ming Gao
    Affiliations
    CAS Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Ke Yuan
    Affiliations
    School of Computing Science and Institute of Cancer Science, University of Glasgow, United Kingdom
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  • Jian Zhou
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China

    Cancer Center, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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  • Jia Fan
    Correspondence
    Corresponding authors. Addresses: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Tel./fax: +86 21 64037181 (Q. Gao), or School of Mathematical Sciences and Center for Statistical Science, Peking University, 5 Yiheyuan Road, Beijing 100871, China (R. Xi), or Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China (J. Fan).
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China

    Cancer Center, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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  • Ruibin Xi
    Correspondence
    Corresponding authors. Addresses: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Tel./fax: +86 21 64037181 (Q. Gao), or School of Mathematical Sciences and Center for Statistical Science, Peking University, 5 Yiheyuan Road, Beijing 100871, China (R. Xi), or Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China (J. Fan).
    Affiliations
    School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, China
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  • Qiang Gao
    Correspondence
    Corresponding authors. Addresses: Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Tel./fax: +86 21 64037181 (Q. Gao), or School of Mathematical Sciences and Center for Statistical Science, Peking University, 5 Yiheyuan Road, Beijing 100871, China (R. Xi), or Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China (J. Fan).
    Affiliations
    Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, China

    State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China
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  • Author Footnotes
    † These authors contributed equally to this work.
Published:March 15, 2018DOI:https://doi.org/10.1016/j.jhep.2018.02.029

      Highlights

      • Branch evolution is the predominant pattern in ICC, collectively shaped by parallel evolution and chromosome instability.
      • ICC may metastasize through polyclonal seeding.
      • Competition between subclonal populations can be used to develop new treatment strategies, like adaptive therapy.
      • Targeted therapy against truncal alterations is a promising treatment strategy.

      Background & Aims

      Intrahepatic cholangiocarcinoma (ICC) is the second-most lethal primary liver cancer. Little is known about intratumoral heterogeneity (ITH) and its impact on ICC progression. We aimed to investigate the ITH of ICC in the hope of helping to develop new therapeutic strategies.

      Methods

      We obtained 69 spatially distinct regions from six operable ICCs. Patient-derived primary cancer cells (PDPCs) were established for each region, followed by whole-exome sequencing (WES) and multi-level validation.

      Results

      We observed widespread ITH for both somatic mutations and clonal architecture, shaped by multiple mechanisms, like clonal “illusion”, parallel evolution and chromosome instability. A median of 60.3% of mutations were heterogeneous, among which 85% of the driver mutations were located on the branches of tumor phylogenetic trees. Many truncal and clonal driver mutations occurred in tumor suppressor genes, such as TP53, SMARCB1 and PBRM1 that are involved in DNA repair and chromatin-remodeling. Genome doubling occurred in most cases (5/6) after the accumulation of truncal mutations and was shared by all intratumoral sub-regions. In all cases, ongoing chromosomal instability is evident throughout the evolutionary trajectory of ICC. The recurrence of ICC1239 provided evidence to support the polyclonal metastatic seeding in ICC. The change of mutation landscape and internal diversity among subclones during metastasis, such as the loss of chemoresistance mediator, can be used for new treatment strategies. Targeted therapy against truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, was developed in 5/6 patients.

      Conclusions

      Integrated investigations of spatial ITH and clonal evolution may provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ICC.

      Lay summary

      We applied multiregional whole-exome sequencing to investigate the evolution of intrahepatic cholangiocarcinoma (ICC). The results revealed that many factors, such as parallel evolution and chromosome instability, may participate and promote the branch diversity of ICC. Interestingly, in one patient with primary and recurrent metastatic tumors, we found evidence of polyclonal metastatic seeding, indicating that symbiotic communities of multiple clones existed and were maintained during metastasis. More realistically, some truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be promising treatment targets in patients with ICC.

      Graphical abstract

      Keywords

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