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The malignant trajectory from the notochord to chordoma and the role of the TBXT rs2305089 germline single nucleotide polymorphism

ABSTRACT: The rare bone cancer chordoma and its putative precursor the Benign Notochordal Cell Tumor (BNCT) express the notochordal transcription factor, TBXT. The aim of this study was to elucidate the role of rs2305089 germline single nucleotide polymorphism in TBXT in the pathogenesis of chordoma. A radiological and genotyping association study demonstrated that BNCTs are associated with chordomas (P<0.001) and with the rs2305089 polymorphism (P=0.002). We then engineered mesoderm/notochord models which differed only by their rs2305089 genotype. Expression of TBXT was higher and the gene regulatory network activated by TBXT was enriched in heterozygous compared to wild type cell lines. Heterozygous cell lines displayed enrichment of Wnt/beta-catenin and epithelial mesenchymal transition pathways while wild type cell lines were enriched for metabolic pathways and MTORC1 signalling. Moreover, the variant A allele induced faster cell migratory capacity together with changes in the expression of endoplasmic reticulum and intracellular transport mediators, thus suggesting that rs2305089 regulates notochord vacuoles as lysosome-related organelles in the aberrant regression of the notochord. In conclusion, we show for the first time that the rs2305089 variant allele is associated not only with chordoma but also with the BNCT and provide functional evidence that this SNP regulates notochordal cell differentiation in the pathogeneis of BNCTs and chordomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277707 | GEO | 2025/03/28

REPOSITORIES: GEO

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Project description:Chordomas are rare tumors of notochord remnants, occurring mainly in the sacrum and skull base. Despite of their unusually slow growth, chordomas are highly invasive and the involvement of adjacent critical structures causes treatment challenges. Due to the low incidence, the molecular pathogenesis of this entity remains largely unknown. This study aimed to investigate DNA methylation abnormalities and their impact on gene expression profiles in skull base chordomas. 32 tumor and 4 normal nucleus pulposus samples were subjected to DNA methylation and gene expression profiling with methylation microarrays and RNA sequencing. Genome-wide DNA methylation analysis revealed two distinct clusters for chordoma (termed subtypes C and I) with different patterns of aberrant DNA methylation. C Chordomas were characterized by general hypomethylation with hypermethylation of CpG islands, while I chordomas were generally hypermethylated. These differences were reflected by distinct distribution of differentially methylated probes (DMPs). Differentially methylated regions (DMRs) were identified, indicating aberrant methylation in known tumor-related genes in booth chordoma subtypes and regions encoding small RNAs in subtype C chordomas. Correlation between methylation and expression was observed in a minority of genes. Upregulation of TBXT in chordomas appeared to be related to lower methylation of tumor-specific DMR in gene promoter. Gene expression-based clusters of tumor samples did not overlap with DNA methylation-based subtypes. Nevertheless, they differ in transcriptomic profile that shows immune infiltration in I chordomas and up-regulation of cell cycle in C chordomas. Immune enrichment in chordomas I was confirmed with 3 independent deconvolution methods and immunohistochemistry. Copy number analysis showed higher chromosomal instability in C chordomas. Nine out of eight had deletion of CDKN2A/B loci and downregulation of genes encoded in related chromosomal band. No significant difference in patients’ survival was observed between tumor subtypes, however, shorter survival was observed in patients with higher number of copy number alterations.

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The malignant trajectory from the notochord to chordoma and the role of the TBXT rs2305089 germline single nucleotide polymorphism

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