Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility.
Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility.
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与脊索瘤相关基因和脊全瘤敏感性中的罕见种系变异。
DOI：
10.3390/cancers13112704
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发表时间：
2021-05-30
期刊：
影响因子：
5.2
通讯作者：
Goldstein AM
中科院分区：
文献类型：
--
作者：
Yepes S;Shah NN;Bai J;Koka H;Li C;Gui S;McMaster ML;Xiao Y;Jones K;Wang M;Vogt A;Zhu B;Zhu B;Hutchinson A;Yeager M;Hicks B;Carter B;Freedman ND;Beane-Freeman L;Chanock SJ;Zhang Y;Parry DM;Yang XR;Goldstein AM
脊索瘤是一种极其罕见的骨癌，尚未得到充分的表征，也几乎没有确定危险因素，这突出表明我们需要提高对疾病生物学的了解。我们的研究旨在通过调查 138 名欧洲血统脊索瘤患者种系 DNA 上涉及脊索瘤相关信号通路和其他生物过程的 265 个基因，与内部对照数据集和一般人群数据库进行比较，以确定脊索瘤易感基因。结果与 80 名中国血统的颅底脊索瘤患者的全基因组测序数据进行了交叉分析。两个数据集中的脊索瘤病例中都丰富了几种罕见的功能丧失和预测的有害错义变异，这表明可能涉及脊索瘤发展和易感性的复杂途径模型，值得在更大规模的研究中进行进一步研究。背景：脊索瘤是一种罕见的骨癌，病因不明。 TBXT是迄今为止唯一确定的脊索瘤易感基因； TBXT 种系单核苷酸变异和拷贝数变异与家族性和散发性脊索瘤的易感性有关。然而，脊索瘤的遗传易感性仍然很大程度上未知。在这项研究中，我们研究了北美和中国脊索瘤患者中涉及 TBXT/脊索瘤相关信号通路和其他生物过程的基因的罕见种系遗传变异。方法：我们鉴定了一般人群和内部对照数据集中非常罕见的变异，并在 138 名欧洲血统脊索瘤患者的全外显子组测序 (WES) 数据集中和 80 名中国颅底脊索瘤患者的全基因组测序 (WGS) 数据集中显示了 265 个基因的致病性证据。结果：138 名欧洲血统患者中的 32 名 (23%) 鉴定出了罕见且可能的致病性变异，包括脊索发育、PI3K/AKT/mTOR、Sonic Hedgehog、SWI/SNF 复合体和中胚层发育途径的一部分基因。在中国患者中也观察到了 COL2A1、EXT1、PDK1、LRP2、TBXT 和 TSC2 等罕见致病变异。结论：我们在脊索瘤患者的种系 DNA 中发现了几种罕见的功能丧失并预测了有害的错义变异，这可能会影响脊索瘤的易感性并反映复杂的易感性，值得在大型研究中进一步研究。
Chordoma is an extremely rare bone cancer that has not been fully characterized and few risk factors have been identified, highlighting the need for improving our understanding of the disease biology. Our study aims to identify chordoma susceptibility genes by investigating 265 genes involved in chordoma-related signaling pathways and other biological processes on germline DNA of 138 chordoma patients of European ancestry compared to internal control datasets and general population databases. Results were intersected with whole genome sequencing data from 80 skull-base chordoma patients of Chinese ancestry. Several rare loss-of-function and predicted deleterious missense variants were enriched in chordoma cases in both datasets, suggesting a complex model of pathways potentially involved in chordoma development and susceptibility, warranting further investigation in larger studies. Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.
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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：
2.5
作者：
Choi, Kyung-Suk;Cohn, Martin J.;Harfe, Brian D.
通讯作者：
Harfe, Brian D.
影响因子：
5.3
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
通讯作者：
Yang XR
影响因子：
4.1
作者：
Hsu W;Mohyeldin A;Shah SR;ap Rhys CM;Johnson LF;Sedora-Roman NI;Kosztowski TA;Awad OA;McCarthy EF;Loeb DM;Wolinsky JP;Gokaslan ZL;Quiñones-Hinojosa A
通讯作者：
Quiñones-Hinojosa A
DOI：
10.1016/s0197-2456(00)00097-0
发表时间：
2000-12-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
Gohagan, JK;Prorok, PC;Kramer, BS
通讯作者：
Kramer, BS