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Genomic spectra of biliary tract cancer

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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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Figure 1: Mutational spectra in BTC.
Figure 2: FGFR2 fusion genes in BTC.
Figure 3: Molecular alterations of cAMP-dependent protein kinase signaling components in BTC.
Figure 4: Driver gene landscape in BTC.
Figure 5: Organ-specific spectra of molecular alterations in oncogenic modules.
Figure 6: Prognostic classification of BTC is associated with genetic and immunological phenotypes.
Figure 7: Molecular spectra of BTC.

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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.

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Authors and Affiliations

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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.

Corresponding author

Correspondence to Tatsuhiro Shibata.

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Nakamura, H., Arai, Y., Totoki, Y. et al. Genomic spectra of biliary tract cancer. Nat Genet 47, 1003–1010 (2015). https://doi.org/10.1038/ng.3375

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