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Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer

Abstract

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.

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Figure 1: Protein expression and functional studies.

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Acknowledgements

Funding was provided by the Wellcome Trust. G.v.H. is supported by an EMBO fellowship and P.J.C. by a Kay Kendall Leukaemia Fund fellowship. R.A.D. is supported by the Robert A. and Renee E. Belfer Foundation for Innovative Cancer Science. G.T. is supported by a fellowship from the Leukemia and Lymphoma Society. GlaxoSmithKline provided support for the SNP 6.0 microarray analyses. UTX antibodies were a kind gift from E. Canaani (Weizmann Institute of Science).

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Authors

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G.v.H., G.L.D. and H.D. performed the functional work and directed the analytical aspects of the study. L.C. performed the expression analyses. C.G. contributed statistical analyses. G.B., S.E., C.H., S.O., J.T., A.B., J.H., C. Latimer, J.A., S.B., D.B., G.B., P.J.C., J.C., S.F., M.J., D.J., C.Y.K., C. Leroy, M.-L.L., D.J.M., S.M., K.M., A. Menzies, T.M., L. Mulderrig, L. Mudie, E.P., R. Shepherd, R. Smith, L.S., P.S., G. Tang, P.S.T., R.T., K.T., J.V., S. West, S. Widaa, P.W., and M.M. performed the sequencing, copy number and data analyses. V.P.C., K.I., S.L., J.W., S.T.Y., S.Y.L., G. Tonon, R.A.D., Y.-T.T., K.C.A., R.J.K., A. Massie, S.K.K. and B.T.T. contributed samples, data and comments on the manuscript. M.R.S. and P.A.F. conceived and directed the study and wrote the manuscript.

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Correspondence to Michael R Stratton or P Andrew Futreal.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figure 1 and Supplementary Tables 1–5 (PDF 1533 kb)

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van Haaften, G., Dalgliesh, G., Davies, H. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 41, 521–523 (2009). https://doi.org/10.1038/ng.349

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