Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Genomic spectra of biliary tract cancer

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).

    Article  PubMed  Google Scholar 

  2. Patel, T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2, 10 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tyson, G.L. & El-Serag, H.B. Risk factors for cholangiocarcinoma. Hepatology 54, 173–184 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Rizvi, S. & Gores, G.J. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145, 1215–1229 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Razumilava, N. & Gores, G.J. Cholangiocarcinoma. Lancet 383, 2168–2179 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Misra, S., Chaturvedi, A., Misra, N.C. & Sharma, I.D. Carcinoma of the gallbladder. Lancet Oncol. 4, 167–176 (2003).

    Article  PubMed  Google Scholar 

  7. Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chan-On, W. et al. Exome sequencing identifies distinct mutational patterns in liver fluke–related and non-infection-related bile duct cancers. Nat. Genet. 45, 1474–1478 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Li, M. et al. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat. Genet. 46, 872–876 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Wu, Y.M. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3, 636–647 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Arai, Y. et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 59, 1427–1434 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Honeyman, J.N. et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343, 1010–1014 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Seshagiri, S. et al. Recurrent R-spondin fusions in colon cancer. Nature 488, 660–664 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. 91, 1310–1316 (1999).

  15. Pilarski, R. et al. Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosom. Cancer 53, 177–182 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Saha, S.K. et al. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 513, 110–114 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Totoki, Y. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 46, 1267–1273 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Ojesina, A.I. et al. Landscape of genomic alterations in cervical carcinomas. Nature 506, 371–375 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Chen, C.R., Kang, Y., Siegel, P.M. & Massagué, J. E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression. Cell 110, 19–32 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Shi, J. et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 27, 2648–2662 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tumeh, P.C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Burns, M.B., Temiz, N.A. & Harris, R.S. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat. Genet. 45, 977–983 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N. Engl. J. Med. 370, 1019–1028 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kirschner, L.S. et al. Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex. Nat. Genet. 26, 89–92 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Huch, M. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. de Visser, K.E., Eichten, A. & Coussens, L.M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 6, 24–37 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Rizvi, N.A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Mermel, C.H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Olshen, A.B., Venkatraman, E.S., Lucito, R. & Wigler, M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004).

    Article  PubMed  Google Scholar 

  35. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S.L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Alexandrov, L.B. et al. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3, 246–259 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Brunet, J.P. et al. Metagenes and molecular pattern discovery using matrix factorization. Proc. Natl. Acad. Sci. USA 101, 4164–4169 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Babur, Ö. et al. Systematic identification of cancer driving signaling pathways based on mutual exclusivity of genomic alterations. Genome Biol. 16, 45 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Leiserson, M.D., Blokh, D., Sharan, R. & Raphael, B.J. Simultaneous identification of multiple driver pathways in cancer. PLOS Comput. Biol. 9, e1003054 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mo, Q. et al. Pattern discovery and cancer gene identification in integrated cancer genomic data. Proc. Natl. Acad. Sci. USA 110, 4245–4250 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–16 and Supplementary Note. (PDF 6610 kb)

Supplementary Tables 1–21

Supplementary Tables 1–21. (XLSX 3019 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing