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T (brachyury) gene duplication confers major susceptibility to familial chordoma


Using high-resolution array-CGH, we identified unique duplications of a region on 6q27 in four multiplex families with at least three cases of chordoma, a cancer of presumed notochordal origin. The duplicated region contains only the T (brachyury) gene, which is important in notochord development and is expressed in most sporadic chordomas. Our findings highlight the value of screening for complex genomic rearrangements in searches for cancer-susceptibility genes.

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Figure 1: Duplications of 6q27 region in individuals with chordoma from families 1, 3, 4 and 8 detected by custom fine-tiling CGH array.

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We thank D. Zametkin for her outstanding skills as a research nurse; G.M. Glenn and M.L. McMaster for their careful clinical evaluations of affected individuals and family members; N.J. Patronas for reviewing the MRIs; A. Bergen and S. Chanock for SNP genotyping; K. Haque and D. Maeder for technical assistance; and, especially, the affected individuals and their families for their participation. This work was supported by the intramural research program of the US National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health; by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development program; and by a grant from the Chordoma Foundation (M.J.K.).

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Authors and Affiliations



X.R.Y. wrote the first draft of the paper; X.R.Y. and D.N. analyzed the data; D.N., S.L., M.J.K. and D.A.A. performed the laboratory studies, including genotyping, sequencing and breakpoint evaluation; D.N. designed and conducted qPCR analyses; D.M.P. initiated the clinical study and evaluated the chordoma-affected families with D.N.; D.M.P., E.S. and N.J.L. collected the families; X.R.Y., D.N., M.J.K., D.M.P. and A.M.G. planned the work and interpreted the results. All authors contributed to the final version of the paper.

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Correspondence to Dilys M Parry.

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Supplementary Methods, Supplementary Tables 1 and 2 and Supplementary Figures 1–3 (PDF 2096 kb)

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Yang, X., Ng, D., Alcorta, D. et al. T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet 41, 1176–1178 (2009).

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