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