Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma.
Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma.
复制标题
DOI：
10.1007/s00439-014-1463-z
复制
发表时间：
2014-10
期刊：
影响因子：
5.3
通讯作者：
Yang XR
中科院分区：
文献类型：
--
作者：
Kelley MJ;Shi J;Ballew B;Hyland PL;Li WQ;Rotunno M;Alcorta DA;Liebsch NJ;Mitchell J;Bass S;Roberson D;Boland J;Cullen M;He J;Burdette L;Yeager M;Chanock SJ;Parry DM;Goldstein AM;Yang XR
脊索瘤是一种罕见的骨癌，被认为起源于脊索残余物。我们之前已经确定种系T复制是几个脊索瘤家族的主要易感机制。最近，一种常见的T基因变异（rs2305089）与散发性脊索瘤的风险显著相关。我们对来自8个脊索瘤家族（3个有T重复）的24个家族病例和54个未受影响的家庭成员、103个散发病例和160个无关对照的所有T外显子进行了测序。我们还测量了所有散发病例的T拷贝数变异。我们证实先前报道的rs2305089变异与家族性[比值比(OR) = 2.6, 95%可信区间(CI) = 0.93, 7.25, P = 0.067]和散发性脊索瘤（OR = 2.85, 95% CI = 1.89, 4.29, P < 0.0001）的风险相关。我们还发现了第二个常见变异rs1056048，它与脊索瘤在家族中密切相关（OR = 4.14, 95% CI = 1.43, 11.92, P = 0.0086）。在散发病例中，另一种常见变异（rs3816300）与rs2305089联合分析时与风险显著相关。在早期发病的病例中，与rs3816300的关联明显更强。此外，我们还发现了仅在散发性脊索瘤病例中观察到的三种罕见变异，所有这些变异都具有基于计算机预测的潜在功能相关性。最后，我们没有在任何散发性脊索瘤病例中观察到T重复。我们的研究结果进一步强调了T基因在家族性和散发性脊索瘤发病机制中的重要性，并提示与T相关的复杂易感性。
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.
登录
查看更多内容
影响因子：
7.3
作者：
Presneau, Nadege;Shalaby, Asem;Flanagan, Adrienne M.
通讯作者：
Flanagan, Adrienne M.
影响因子：
6.2
作者：
Smoll, Nicolas R.;Gautschi, Oliver P.;Weber, Damien C.
通讯作者：
Weber, Damien C.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
11.4
作者：
KISPERT, A;KOSCHORZ, B;HERRMANN, BG
通讯作者：
HERRMANN, BG