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Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases1,2, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification—SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase—as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported3. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.

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Figure 1: Gene expression analysis reveals two main classes of tumours: hypoxic and non-hypoxic.
Figure 2: Gene deregulation in SETD2 and JARID1C mutant samples.

Accession codes

Primary accessions

ArrayExpress

Gene Expression Omnibus

Data deposits

The patient and cell line expression data were deposited with the Gene Expression Omnibus and Array Express under accession numbers GSE17895 and E-TABM-770, respectively.

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Acknowledgements

We would like to acknowledge the Wellcome Trust for support under grant reference 077012/Z/05/Z and the Hauenstein and Gerber Foundations for support for the microarray expression work. We also thank S. Martin, W. McLaughlin and S. Noyes for administrative support and F. Brasseur for providing the matched-pair ccRCC cell lines.

Author Contributions G.L.D. directed the analytical aspects of the study. K.F., K.J.D. and L.C. performed the expression analyses. C.G. contributed statistical analyses. G.B., H.D., S.E., C.H., J.T., A.B., Je.A., S.B., D.B., G.B., P.J.C., S.F., M.J., D.J., H.K., C.Y.K., C.L., M.-L.L., D.J.M., M.M., S.M., K.M., A.M., T.M., Le.M., La.M., S.O., E.P., A.R., Re.S., Ra.S., L.S., P.S., G.T., P.S.T. and K.T. performed the sequencing, copy number, data analyses and provided comments on the manuscript. Jo.A., R.J.K., S.K.K., D.P., B.W. 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 Bin Tean Teh, Michael R. Stratton or P. Andrew Futreal.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Data, Supplementary References and Supplementary Figures 1-3 with Legends. (PDF 1823 kb)

Supplementary Dataset 1

Germline variants. (PDF 386 kb)

Supplementary Dataset 2

Gene expression. (PDF 1109 kb)

Supplementary Table 1

This table contains the initial and follow up samples that were screened. (XLS 58 kb)

Supplementary Table 2

This table shows the ID of the genes sequenced. (XLS 333 kb)

Supplementary Table 3

In this table the initial screen somatic mutations are identified. (XLS 227 kb)

Supplementary Table 4

This table shows the mutation prevalence. (PDF 43 kb)

Supplementary Table 5

This table shows the genes sequenced in follow-up samples. (XLS 33 kb)

Supplementary Table 6

In this table the follow-up screen somatic mutations are identified. (XLS 128 kb)

Supplementary Table 7

This table contains the statistical analyses data. (XLS 567 kb)

Supplementary Table 8

This table shows the details of mutations in highlighted genes. (XLS 134 kb)

Supplementary Table 9

In this table the JARID1C, SETD2 cancer cell line screen variants are identified. (XLS 34 kb)

Supplementary Table 10

This table contains SETD2 and JARID1C expression analyses. (XLS 128 kb)

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Dalgliesh, G., Furge, K., Greenman, C. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010). https://doi.org/10.1038/nature08672

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