Usher Inga, O'Donnell Paul, Ligammari Lorena, Harder Dorothee, Brown Wendy, Choi David, Cool Paul, Cottone Lucia, Flanagan Adrienne M
Department of Pathology, University College London Cancer Institute, London, UK.
Victor Horsley Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery, London, UK.
J Pathol. 2025 Jul;266(3):247-257. doi: 10.1002/path.6427. Epub 2025 May 5.
The aim of this research was to investigate the pathogenesis of the bone cancer chordoma and the role of the germline rs2305089 SNP in TBXT. Using medical imaging and genotyping studies, we observed that benign notochordal cell tumours (BNCTs) were associated with chordomas and with the variant rs2305089 A-allele with enrichment of the AA genotype compared to controls. We engineered in vitro mesoderm models, representing notochord, which showed higher expression of TBXT and activation of its regulatory network in the presence of the variant A allele. Heterozygotes (GA) displayed enrichment of Wnt/β-catenin and epithelial mesenchymal transition pathways, faster cell migratory capacity, and altered expression of endoplasmic reticulum and intracellular transport mediators. WT lines (GG) were enriched for metabolic pathways and MTORC1 signalling, suggesting that rs2305089 genotype regulates notochord vacuoles during notochord regression. By leveraging patient-derived data and functional studies, we show that the variant rs2305089 A-allele predisposes to BNCTs and ultimately to chordomas. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
本研究的目的是调查骨癌脊索瘤的发病机制以及种系rs2305089单核苷酸多态性在TBXT中的作用。通过医学成像和基因分型研究，我们观察到良性脊索细胞瘤（BNCTs）与脊索瘤以及rs2305089 A等位基因变异相关，与对照组相比，AA基因型富集。我们构建了代表脊索的体外中胚层模型，其显示在存在变异A等位基因的情况下，TBXT表达更高且其调控网络被激活。杂合子（GA）显示Wnt/β-连环蛋白和上皮-间质转化途径富集，细胞迁移能力更快，内质网和细胞内运输介质的表达改变。野生型系（GG）在代谢途径和MTORC1信号传导方面富集，这表明rs2305089基因型在脊索退化过程中调节脊索空泡。通过利用患者来源的数据和功能研究，我们表明rs2305089 A等位基因变异易患BNCTs并最终易患脊索瘤。© 2025作者。《病理学杂志》由约翰·威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
