Yepes Sally, Shah Nirav N, Bai Jiwei, Koka Hela, Li Chuzhong, Gui Songbai, McMaster Mary Lou, Xiao Yanzi, Jones Kristine, Wang Mingyi, Vogt Aurelie, Zhu Bin, Zhu Bin, Hutchinson Amy, Yeager Meredith, Hicks Belynda, Carter Brian, Freedman Neal D, Beane-Freeman Laura, Chanock Stephen J, Zhang Yazhuo, Parry Dilys M, Yang Xiaohong R, Goldstein Alisa M
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Beijing Tiantan Hospital, Beijing 100070, China.
Cancers (Basel). 2021 May 30;13(11):2704. doi: 10.3390/cancers13112704.
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.
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.
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.
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.
脊索瘤是一种病因不明的罕见骨癌。TBXT是迄今为止唯一被鉴定出的脊索瘤易感基因；TBXT中的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相关。然而，脊索瘤的遗传易感性在很大程度上仍不清楚。在本研究中，我们调查了北美和中国脊索瘤患者中参与TBXT/脊索瘤相关信号通路及其他生物学过程的基因中的罕见种系遗传变异。
我们在138名欧洲血统的脊索瘤患者的全外显子测序（WES）数据集以及80名中国颅底脊索瘤患者的全基因组测序（WGS）数据集中，鉴定出在一般人群和内部对照数据集中非常罕见且有致病性证据的265个基因中的变异。
在138名欧洲血统患者中的32名（23%）中鉴定出罕见且可能致病的变异，包括参与脊索发育、PI3K/AKT/mTOR、音猬因子、SWI/SNF复合物和中胚层发育通路的基因。在中国患者中也观察到COL2A1、EXT1、PDK1、LRP2、TBXT和TSC2等基因中的罕见致病变异。
我们在脊索瘤患者的种系DNA中鉴定出了几种罕见的功能丧失和预测有害的错义变异，这些变异可能影响脊索瘤易感性并反映出复杂的易感性，值得在大型研究中进一步研究。
