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Abstract

The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor–mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.

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Acknowledgements

This study was supported by Grants-in-Aid from the Ministry of Health, Labour and Welfare and the Japan Agency for Medical Research and Development (Health and Labour Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer), National Cancer Center Research and Development Funds (26-A-5), MEXT KAKENHI (grant 26461040) and the Yasuda Medical Foundation. The National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan. The supercomputing resource 'SHIROKANE' was provided by the Human Genome Center, The University of Tokyo.

Author information

Author notes

    • Hiromi Nakamura
    • , Yasuhito Arai
    • , Yasushi Totoki
    • , Tomoki Shirota
    •  & Asmaa Elzawahry

    These authors contributed equally to this work.

Affiliations

  1. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.

    • Hiromi Nakamura
    • , Yasuhito Arai
    • , Yasushi Totoki
    • , Tomoki Shirota
    • , Asmaa Elzawahry
    • , Natsuko Hama
    • , Fumie Hosoda
    • , Shoko Ohashi
    •  & Tatsuhiro Shibata
  2. First Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.

    • Tomoki Shirota
    •  & Shinichi Miyagawa
  3. Department of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan.

    • Mamoru Kato
  4. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

    • Tomoko Urushidate
    •  & Tatsuhiro Shibata
  5. Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.

    • Nobuyoshi Hiraoka
    •  & Hidenori Ojima
  6. Department of Pathology, Keio University School of Medicine, Tokyo, Japan.

    • Hidenori Ojima
  7. Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan.

    • Kazuaki Shimada
    •  & Tomoo Kosuge
  8. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

    • Takuji Okusaka

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Contributions

Study design: Y.A., Y.T. and T. Shibata. Sequence data production: T. Shirota, F.H., T.U. and S.O. Data analysis: H.N., Y.T., A.E., M.K. and N. Hama Statistical analysis: H.N., Y.T., A.E., M.K. and N. Hama Molecular analysis: Y.A. and F.H. Sample acquisition and clinical data collection: T. Shirota, N. Hiraoka, H.O., K.S., T.O., T.K. and S.M. Manuscript writing: H.N., Y.A., Y.T., M.K., F.H. and T. Shibata. Project oversight: Y.A., Y.T. and T. Shibata.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tatsuhiro Shibata.

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DOI

https://doi.org/10.1038/ng.3375

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