Abstract
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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References
Chadwick LH (2012) The NIH Roadmap Epigenomics Program data resource. Epigenomics 4(3):317–324. doi:10.2217/epi.12.18
Chambers KJ, Lin DT, Meier J, Remenschneider A, Herr M, Gray ST (2013) Incidence and survival patterns of cranial chordoma in the United States. Laryngoscope. doi:10.1002/lary.24420
Cheng J, Randall A, Baldi P (2006) Prediction of protein stability changes for single-site mutations using support vector machines. Proteins 62(4):1125–1132. doi:10.1002/prot.20810
DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43(5):491–498. doi:10.1038/ng.806
Healey JH, Lane JM (1989) Chordoma: a critical review of diagnosis and treatment. Orthop Clin North Am 20(3):417–426
Kispert A, Herrmann BG (1994) Immunohistochemical analysis of the Brachyury protein in wild-type and mutant mouse embryos. Dev Biol 161(1):179–193. doi:10.1006/dbio.1994.1019
Kispert A, Koschorz B, Herrmann BG (1995) The T protein encoded by Brachyury is a tissue-specific transcription factor. EMBO J 14(19):4763–4772
McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM (2001) Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control 12(1):1–11
Muller CW, Herrmann BG (1997) Crystallographic structure of the T domain-DNA complex of the Brachyury transcription factor. Nature 389(6653):884–888. doi:10.1038/39929
Pfeiffer RM, Gail MH, Pee D (2001) Inference for covariates that accounts for ascertainment and random genetic effects in family studies. Biometrika 88:16
Pillay N, Plagnol V, Tarpey PS, Lobo SB, Presneau N, Szuhai K, Halai D, Berisha F, Cannon SR, Mead S, Kasperaviciute D, Palmen J, Talmud PJ, Kindblom LG, Amary MF, Tirabosco R, Flanagan AM (2012) A common single-nucleotide variant in T is strongly associated with chordoma. Nat Genet 44(11):1185–1187. doi:10.1038/ng.2419
Presneau N, Shalaby A, Ye H, Pillay N, Halai D, Idowu B, Tirabosco R, Whitwell D, Jacques TS, Kindblom LG, Bruderlein S, Moller P, Leithner A, Liegl B, Amary FM, Athanasou NN, Hogendoorn PC, Mertens F, Szuhai K, Flanagan AM (2011) Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study. J Pathol 223(3):327–335. doi:10.1002/path.2816
Rich TA, Schiller A, Suit HD, Mankin HJ (1985) Clinical and pathologic review of 48 cases of chordoma. Cancer 56(1):182–187
Rosenbloom KR, Sloan CA, Malladi VS, Dreszer TR, Learned K, Kirkup VM, Wong MC, Maddren M, Fang R, Heitner SG, Lee BT, Barber GP, Harte RA, Diekhans M, Long JC, Wilder SP, Zweig AS, Karolchik D, Kuhn RM, Haussler D, Kent WJ (2013) ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res 41 (Database issue):D56–63. doi:10.1093/nar/gks1172
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575–576. doi:10.1038/nmeth0810-575
Smoll NR, Gautschi OP, Radovanovic I, Schaller K, Weber DC (2013) Incidence and relative survival of chordomas: the standardized mortality ratio and the impact of chordomas on a population. Cancer 119(11):2029–2037. doi:10.1002/cncr.28032
Tai PT, Craighead P, Bagdon F (1995) Optimization of radiotherapy for patients with cranial chordoma. A review of dose-response ratios for photon techniques. Cancer 75(3):749–756
Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM (2006) Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol 209(2):157–165. doi:10.1002/path.1969
Wu Z, Wang K, Wang L, Feng J, Hao S, Tian K, Zhang L, Jia G, Wan H, Zhang J (2013) The Brachyury Gly177Asp SNP is not associated with a risk of skull base chordoma in the Chinese population. Int J Mol Sci 14(11):21258–21265. doi:10.3390/ijms141121258
Yang XHR, Ng D, Alcorta DA, Liebsch NJ, Sheridan E, Li SF, Goldstein AM, Parry DM, Kelley MJ (2009) T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet 41(11):1176–1178. doi:10.1038/Ng.454
Yang J, Manolio TA, Pasquale LR, Boerwinkle E, Caporaso N, Cunningham JM, de Andrade M, Feenstra B, Feingold E, Hayes MG, Hill WG, Landi MT, Alonso A, Lettre G, Lin P, Ling H, Lowe W, Mathias RA, Melbye M, Pugh E, Cornelis MC, Weir BS, Goddard ME, Visscher PM (2011) Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet 43(6):519–525. doi:10.1038/ng.823
Acknowledgments
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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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). https://doi.org/10.1007/s00439-014-1463-z
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DOI: https://doi.org/10.1007/s00439-014-1463-z