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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011).
Patel, T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2, 10 (2002).
Tyson, G.L. & El-Serag, H.B. Risk factors for cholangiocarcinoma. Hepatology 54, 173–184 (2011).
Rizvi, S. & Gores, G.J. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145, 1215–1229 (2013).
Razumilava, N. & Gores, G.J. Cholangiocarcinoma. Lancet 383, 2168–2179 (2014).
Misra, S., Chaturvedi, A., Misra, N.C. & Sharma, I.D. Carcinoma of the gallbladder. Lancet Oncol. 4, 167–176 (2003).
Alexandrov, L.B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
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).
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).
Wu, Y.M. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3, 636–647 (2013).
Arai, Y. et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 59, 1427–1434 (2014).
Honeyman, J.N. et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343, 1010–1014 (2014).
Seshagiri, S. et al. Recurrent R-spondin fusions in colon cancer. Nature 488, 660–664 (2012).
Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl. Cancer Inst. 91, 1310–1316 (1999).
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).
Saha, S.K. et al. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 513, 110–114 (2014).
Totoki, Y. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 46, 1267–1273 (2014).
Ojesina, A.I. et al. Landscape of genomic alterations in cervical carcinomas. Nature 506, 371–375 (2014).
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).
Shi, J. et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 27, 2648–2662 (2013).
Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Tumeh, P.C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Burns, M.B., Temiz, N.A. & Harris, R.S. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat. Genet. 45, 977–983 (2013).
Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N. Engl. J. Med. 370, 1019–1028 (2014).
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).
Huch, M. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015).
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).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Rizvi, N.A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348, 124–128 (2015).
Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
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).
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).
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).
Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
Alexandrov, L.B. et al. Deciphering signatures of mutational processes operative in human cancer. Cell Rep. 3, 246–259 (2013).
Brunet, J.P. et al. Metagenes and molecular pattern discovery using matrix factorization. Proc. Natl. Acad. Sci. USA 101, 4164–4169 (2004).
Babur, Ö. et al. Systematic identification of cancer driving signaling pathways based on mutual exclusivity of genomic alterations. Genome Biol. 16, 45 (2015).
Leiserson, M.D., Blokh, D., Sharan, R. & Raphael, B.J. Simultaneous identification of multiple driver pathways in cancer. PLOS Comput. Biol. 9, e1003054 (2013).
Mo, Q. et al. Pattern discovery and cancer gene identification in integrated cancer genomic data. Proc. Natl. Acad. Sci. USA 110, 4245–4250 (2013).
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).
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
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
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
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.3375
This article is cited by
-
Endoscopic ultrasound-guided tissue acquisition for comprehensive genomic profiling
Journal of Medical Ultrasonics (2024)
-
Cell-Free DNA in Plasma Reveals Genomic Similarity Between Biliary Tract Inflammatory Lesion and Biliary Tract Cancer
Phenomics (2024)
-
Molecular profiling and prognostic analysis in Chinese cholangiocarcinoma: an observational, retrospective single-center study
Investigational New Drugs (2024)
-
The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression
Journal of Experimental & Clinical Cancer Research (2023)
-
Oncogenic activation revealed by FGFR2 genetic alterations in intrahepatic cholangiocarcinomas
Cell & Bioscience (2023)