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Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma


Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95 % confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95 % CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95 % CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T.

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We thank Deborah Zametkin for her outstanding skills as a research nurse; Drs. Gladys M. Glenn and Mary L. McMaster for their careful clinical evaluations of patients and family members; Dr. Nicholas J. Patronas for reviewing the MR images; Cancer Genomics Research Laboratory for sequencing and bioinformatic analyses; and, especially, the patients and their families for their participation. This work was supported by the Intramural Research Program of the National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health, and by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development program, and a grant from the Chordoma Foundation (M.J.K.).

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Institutional Review Board, National Cancer Institute.

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Correspondence to Xiaohong R. Yang.

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Kelley, M.J., Shi, J., Ballew, B. et al. Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma. Hum Genet 133, 1289–1297 (2014).

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  • Copy Number Variation
  • Rare Variant
  • Risk Allele
  • Sporadic Case
  • Chordoma