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.

Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas

Abstract

Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Genes with frequent inactivating mutations in intrahepatic cholangiocarcinoma.

References

  1. Everhart, J.E. & Ruhl, C.E. Burden of digestive diseases in the United States Part III: Liver, biliary tract, and pancreas. Gastroenterology 136, 1134–1144 (2009).

    Article  Google Scholar 

  2. Blechacz, B. et al. Clinical diagnosis and staging of cholangiocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 8, 512–522 (2011).

    Article  Google Scholar 

  3. Borger, D.R. et al. Frequent mutation of isocitrate dehydrogenase IDH1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17, 72–79 (2012).

    Article  CAS  Google Scholar 

  4. Voss, J.S. et al. Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum. Pathol. 44, 1216–1222 (2013).

    Article  CAS  Google Scholar 

  5. Xu, R.F. et al. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed. Pharmacother. 65, 22–26 (2011).

    Article  CAS  Google Scholar 

  6. Chuang, S.C. et al. Immunohistochemical study of DPC4 and p53 proteins in gallbladder and bile duct cancers. World J. Surg. 28, 995–1000 (2004).

    Article  Google Scholar 

  7. Tannapfel, A. et al. Genetic and epigenetic alterations of the INK4a-ARF pathway in cholangiocarcinoma. J. Pathol. 197, 624–631 (2002).

    Article  CAS  Google Scholar 

  8. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    Article  CAS  Google Scholar 

  9. Parwani, A.V. et al. Immunohistochemical and genetic analysis of non-small cell and small cell gallbladder carcinoma and their precursor lesions. Mod. Pathol. 16, 299–308 (2003).

    Article  Google Scholar 

  10. Yanagisawa, N. et al. More frequent β-catenin exon 3 mutations in gallbladder adenomas than in carcinomas indicate different lineages. Cancer Res. 61, 19–22 (2001).

    CAS  PubMed  Google Scholar 

  11. Murali, R. et al. Tumours associated with BAP1 mutations. Pathology 45, 116–126 (2013).

    Article  CAS  Google Scholar 

  12. Jones, S. et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum. Mutat. 33, 100–103 (2012).

    Article  CAS  Google Scholar 

  13. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

    Article  CAS  Google Scholar 

  14. Ma, X. et al. Histone deacetylase inhibitors: current status and overview of recent clinical trials. Drugs 69, 1911–1934 (2009).

    Article  CAS  Google Scholar 

  15. Ong, C.K. et al. Exome sequencing of liver fluke–associated cholangiocarcinoma. Nat. Genet. 44, 690–693 (2012).

    Article  CAS  Google Scholar 

  16. Wang, P. et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32, 3091–3100 (2013).

    Article  CAS  Google Scholar 

  17. Pollock, P.M. et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26, 7158–7162 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Sjöblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  Google Scholar 

  20. Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).

    Article  CAS  Google Scholar 

  21. Mielke, P.W. et al. Combining probability values from independent permutation tests: a discrete analog of Fisher's classical method. Psychol. Rep. 95, 449–458 (2004).

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the following funding sources: the Virginia and D.K. Ludwig Fund for Cancer Research; the Lustgarten Foundation for Pancreatic Cancer Research; US National Institutes of Health (NIH) grants P50 CA62924, K08DK090154 and EDRN U01CA086402; Associazione Italiana Ricerca Cancro (AIRC grants 12182, 11930, 6421 and IG 12214); and Italian Cancer Genome Project FIRB RBAP10AHJB.

Author information

Authors and Affiliations

Authors

Contributions

T.M.P., R.A.A., A.S., R.K., V.E.V., R.H.H., B.V., K.W.K., N.P. and L.D.W. jointly supervised research. Y.J., F.M.S., A. Maitra, M.F., M.S., A. Mafficini, P.C., R.T.L., A.R., A.G., G.T., F.d.B., A.S., R.K., V.E.V., R.H.H., B.V., K.W.K., N.P. and L.D.W. conceived and designed experiments. Y.J., M.M.S., A. Maitra, G.J.A.O., J.C.R., L.R.R., G.J.G., I.P., S.T.A., S.D., M.F., M.S., A. Mafficini, P.C., R.T.L., A.R., A.G., G.T., F.d.B., A.S., D.K., B.V., K.W.K., N.P. and L.D.W. performed experiments. T.M.P., R.A.A., D.J.L., N.N., V.B.G., R.K., K.W.K., N.P. and L.D.W. performed statistical analysis. Y.J., T.M.P., R.A.A., D.J.L., N.N., V.B.G., M.F., M.S., A. Mafficini, P.C., R.T.L., A.R., A.G., G.T., F.d.B., A.S., W.J., D.K., R.K., R.H.H., B.V., K.W.K., N.P. and L.D.W. analyzed data. F.M.S., M.M.S., A. Maitra, P.A., G.J.A.O., J.C.R., L.R.R., G.J.G., I.P., S.T.A., S.D., M.F., M.S., A. Mafficini, P.C., R.T.L., A.R., A.G., G.T., F.d.B., A.S., W.J., D.K., R.K., V.E.V., R.H.H., B.V., K.W.K., N.P. and L.D.W. contributed reagents, materials or analysis tools. Y.J., T.M.P., R.A.A., F.M.S., A. Maitra, D.K., R.H.H., B.V., K.W.K., N.P. and L.D.W. wrote the manuscript.

Corresponding authors

Correspondence to Aldo Scarpa, Kenneth W Kinzler, Nickolas Papadopoulos or Laura D Wood.

Ethics declarations

Competing interests

Under agreements between Johns Hopkins University, Genzyme, Myriad Genetics, Exact Sciences, Inostics, Qiagen, Invitrogen and Personal Genome Diagnostics, V.E.V., N.P., B.V., K.W.K. and R.H.H. are entitled to a share of the royalties received by Johns Hopkins University on sales of products related to genes and technologies described in this manuscript. V.E.V., N.P., B.V. and K.W.K. are cofounders of Inostics and Personal Genome Diagnostics, are members of their scientific advisory boards and own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy. L.D.W. is a paid consultant for Personal Genome Diagnostics. The contribution of D.J.L. to this manuscript represents his own views and not the official policy of the US Navy, US Department of Defense or US government.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–3, 5, 6 and 8 and Supplementary Figure 1 (PDF 4658 kb)

Supplementary Table 4

Somatic mutations in intrahepatic cholangiocarcinoma and gallbladder carcinoma (XLSX 126 kb)

Supplementary Table 7

Summary of prevalence screen for intrahepatic cholangiocarcinoma and gallbladder carcinoma (XLSX 24 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jiao, Y., Pawlik, T., Anders, R. et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 45, 1470–1473 (2013). https://doi.org/10.1038/ng.2813

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2813

This article is cited by

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