To systematically explore causal relationships between chondrosarcoma and angiogenesis-related gene expression using Mendelian randomization (MR) and transcriptome-wide association study (TWAS) approaches, and identify potential therapeutic targets. Based on whole blood tissue gene expression data, summary-data-based Mendelian randomization (SMR) analysis was performed to examine causal associations between 25 angiogenesis-related candidate genes and chondrosarcoma risk. Simultaneously, transcriptome-wide association study (TWAS) was conducted covering 22 autosomes, calculating Z-scores and P-values to assess the strength of association between gene expression and disease. Key findings were validated by RT-qPCR in chondrosarcoma cell lines versus normal chondrocytes. SMR analysis identified significant causal associations after correction. LINC00984 showed the strongest risk association (OR = 5.243, P = 1.10 × 10-2), while TXNDC2 also demonstrated risk effects (OR = 3.555, P = 5.09 × 10-3). Protective genes included MPL28 (OR = 0.070, P = 1.40 × 10-2) and RP11-474N24.6 (OR = 0.287, P = 1.92 × 10-3). TWAS identified significant signals on chromosomes 18–19 and 22. Functional analysis confirmed enrichment in VEGF and HIF-1 pathways. RT-qPCR validation showed risk genes were upregulated 3.2–8.2-fold in tumor cells, while protective genes were downregulated 58–78% (all P < 0.01). This study identified multiple angiogenesis-regulatory genes significantly associated with chondrosarcoma through large-scale genetic analysis, revealing complex molecular mechanisms of disease development and providing important genetic evidence for precision therapeutic strategy development.
Xie et al. (2026) studied this question.