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A common single-nucleotide variant in T is strongly associated with chordoma


Chordoma is a rare malignant bone tumor that expresses the transcription factor T. We conducted an association study of 40 individuals with chordoma and 358 ancestry-matched controls, with replication in an independent cohort. Whole-exome and Sanger sequencing of T exons showed strong association of the common nonsynonymous SNP rs2305089 with chordoma risk (allelic odds ratio (OR) = 6.1, 95% confidence interval (CI) = 3.1–12.1; P = 4.4 × 10−9), a finding that is exceptional in cancers with a non-Mendelian mode of inheritance.

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Figure 1: Association of rs2305089 with chordoma and T expression.

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We are grateful to the study subjects for participating in the research and to the clinicians and support staff in the London Sarcoma Service involved in their care. We thank S. McLaren, C. Latimer, K. Raine and A. Butler at the The Wellcome Trust Sanger Institute for assistance with the exome sequencing. We are also grateful to L. Game (Head of Genomics Laboratory, MRC Clinical Sciences Centre) for assistance with aCGH scanning. We are particularly grateful to B. Liegl (Medical University of Graz) for providing us with the chordoma cell line, MUG-Chor1. The research was funded by the Skeletal Cancer Action Trust (SCAT), UK, The Pathological Society (N. Pillay), The Chordoma Foundation, The Rosetrees Foundation and the Wellcome Trust Sanger Institute (grant 98051). The research was part of the RNOH Musculoskeletal Research Programme and Biobank and the UCL Hospital (UCLH)/UCL Comprehensive Biomedical Research Programme and was supported by the UCL Experimental Cancer Centre.

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N. Pillay and A.M.F. conceived and initiated the project and planned the experiments. V.P. and D.K. performed exome sequencing analysis and SNP6.0 array analysis. N. Pillay, D.H., F.B., P.S.T., S.B.L., N. Presneau, K.S. and J.P. performed the experiments. R.T., M.F.A., A.M.F., L.-G.K., P.J.T., S.M. and S.R.C. selected and provided the samples. N. Pillay, A.M.F. and V.P. wrote the manuscript. All authors reviewed and contributed to the final manuscript.

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Correspondence to Adrienne M Flanagan.

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The authors declare no competing financial interests.

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Supplementary Figures 1–8, Supplementary Tables 1–4 and Supplementary Methods (PDF 1562 kb)

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Pillay, N., Plagnol, V., Tarpey, P. et al. A common single-nucleotide variant in T is strongly associated with chordoma. Nat Genet 44, 1185–1187 (2012).

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