title: Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma.
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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, 27705, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelley
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Bari
authors.initials: B
authors.lastname: Ballew
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hyland
authors.forename: Wen-Qing
authors.initials: WQ
authors.lastname: Li
authors.forename: Melissa
authors.initials: M
authors.lastname: Rotunno
authors.forename: David A
authors.initials: DA
authors.lastname: Alcorta
authors.forename: Norbert J
authors.initials: NJ
authors.lastname: Liebsch
authors.forename: Jason
authors.initials: J
authors.lastname: Mitchell
authors.forename: Sara
authors.initials: S
authors.lastname: Bass
authors.forename: David
authors.initials: D
authors.lastname: Roberson
authors.forename: Joseph
authors.initials: J
authors.lastname: Boland
authors.forename: Michael
authors.initials: M
authors.lastname: Cullen
authors.forename: Ji
authors.initials: J
authors.lastname: He
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdette
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Dilys M
authors.initials: DM
authors.lastname: Parry
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: Xiaohong R
authors.initials: XR
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002817:Chordoma / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005326:Fetal Proteins / Q000235:genetics*; D020440:Gene Duplication; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012447:Sacrum; D019292:Skull Base Neoplasms / Q000235:genetics*; D013125:Spinal Neoplasms / Q000235:genetics*; D020825:T-Box Domain Proteins / Q000235:genetics*; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein