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Exome sequencing identifies distinct mutational patterns in liver fluke–related and non-infection-related bile duct cancers

Abstract

The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non–O. viverrini–related etiologies. Whole-exome sequencing (n = 15) and prevalence screening (n = 194) identified recurrent somatic mutations in BAP1 and ARID1A, neither of which, to our knowledge, has previously been reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini–related and non–O. viverrini–related CCAs demonstrated statistically significant differences in mutation patterns: BAP1, IDH1 and IDH2 were more frequently mutated in non–O. viverrini CCAs, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations, even within the same tumor type.

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Figure 1: Somatic mutations in ARID1A and the suppressive role of ARID1A in cell proliferation.
Figure 2: Distribution of BAP1 somatic mutations and the inhibitory function of BAP1 in cell proliferation.

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Acknowledgements

We thank B. Haaland for reviewing all statistical tests performed in this study and the Duke–National University of Singapore Genome Biology Facility for performing whole-exome sequencing and methylation assays. We thank D. Jefferson (New England Medical Center, Tufts University) for the H69 cell line. We thank B. Sripa (Khon Kean University) for the M139 cell line. This work was supported in part by funding from the Singapore National Medical Research Council (NMRC/STAR/0006/2009), the Singapore Millennium Foundation, the Lee Foundation, the Singapore National Cancer Centre Research Fund, the Duke–National University of Singapore Graduate Medical School, the Cancer Science Institute, Singapore, the Verdant Foundation, Hong Kong, Innovation Funding from the Executive Agency for Higher Education, Research and Development, Romania, a Research Team Strengthening Grant, the National Genetic Engineering and Biotechnology Center and the National Science and Technology Development Agency, Thailand. W.Y. is the recipient of a National University of Singapore Graduate School for Integrative Sciences and Engineering scholarship.

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W.C., M.-L.N., C.K.O., I.P., S.G.R., P.T. and B.T.T. conceived the study. I.P., S.G.R., P.T. and B.T.T. directed the study. J.R.M., W.K.L., I.C., S.N. and W.Y. performed the bioinformatics analysis. K.H.L., S.D., D.D., A.C., P.C.C., L.O., P.C., S.Y.L., S.P.C., I.B.H.T., C.P., P.Y., S.W., N.K. and V.B. were involved in the procurement and histopathological review of the samples. P.S. performed ELISAs for O. viverrini antigen detection. S.S.M., A.N., B.H.W. and A.J. were involved in specimen collection and preparation. W.C., M.-L.N., H.L.H., A.G., V.R., C.C.Y.N., A.J., S.Z., P.V. and D.H. performed sequencing and in vitro functional studies. W.C., M.-L.N., C.K.O., W.K.L., S.G.R., P.T. and B.T.T. wrote the manuscript, with the assistance and final approval of all authors.

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Correspondence to Vajaraphongsa Bhudhisawasdi, Irinel Popescu, Steven G Rozen, Patrick Tan or Bin Tean Teh.

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Chan-on, W., Nairismägi, ML., Ong, C. 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). https://doi.org/10.1038/ng.2806

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