Abstract C038: Mitochondrial genetic variation orchestrates COPZ1 transcript heterogeneity and reveals telomere-mediated vulnerabilities in osteosarcoma

Abstract Introduction While telomere biology has been implicated in osteosarcoma, potential connections with mitochondrial function remain unexplored. We investigated causal roles of telomere length and mitochondrial DNA (mtDNA) copy number in osteosarcoma risk and characterized regulatory mechanisms potentially linking these cellular processes. Methods We performed Mendelian randomization using 94 telomere length-associated and 113 mtDNA copy number-associated variants against FinnGen osteosarcoma statistics. Multiple analytical approaches were employed including inverse variance weighted regression, MR-Egger, weighted median, and MR-PRESSO methods. Splicing quantitative trait loci (sQTL) analysis using GTEx v10 skeletal muscle data identified regulatory variants. Variant Effect Predictor (VEP) annotation assessed functional consequences. Expression profiling was conducted in GTEx muscle tissue and 212 osteosarcoma samples from Recount3 (SRP090849). Results Mendelian randomization revealed that genetically determined longer telomeres confer significant protection against osteosarcoma risk (β=-0.5358, 95% CI: -0.72 to -0.36, p=0.0029), with leave-one-out analysis confirming robustness across all variants. In contrast, mtDNA copy number showed no causal association with osteosarcoma risk (β=0.2963, 95% CI: -0.1542 to 0.7468, p=0.511), with consistent null findings across MR-Egger (β= 0.4135, p=0.289) and weighted median (β=0.1405) approaches. Among 113 mitochondrial variants tested, rs11451044 emerged as a significant skeletal muscle-specific sQTL for COPZ1 (slope=-0.2714, 95% CI: -0.3165 to -0.2263, p<0.001), while rs2853828 showed no splicing association (p=0.403). VEP analysis predicted that rs11451044 alters splicing or transcript processing across 18 COPZ1 isoforms. Expression analysis in skeletal muscle identified ENST00000262061.7 as the dominant COPZ1 transcript (mean transcripts per million=48.5). In metastatic osteosarcoma tumor samples, this transcript showed remarkable heterogeneity (range: 18,758-215,617). Length-normalized analysis revealed COPZ1 transcriptional activity 3.3-fold higher than COPZ2 (median: 50,080 vs 14,902 reads/kb). Conclusion Our findings establish telomere length as a protective factor against osteosarcoma risk through Mendelian randomization while revealing no causal role for mtDNA copy number. The identification of rs11451044 as a muscle-specific regulatory variant controlling COPZ1 transcript processing, combined with the substantial expression heterogeneity and dominance of COPZ1 over COPZ2 in osteosarcoma, suggests a regulatory axis where mitochondrial genetic variation influences coatomer function. Given that COPZ2 buffers metabolic stress under normal conditions but is downregulated in tumor cells, the preferential reliance on COPZ1 highlights it as a context-specific vulnerability that may represent a promising therapeutic target in osteosarcoma. Citation Format: Kole Joachim, Adrian Lin, Brandon Gettleman, Christopher Hamad, Amanda Perrotta, Sumin Jeong, Michael Fice, Lauren E. Wessel, Nicholas Bernthal, Alexander B. Christ. Mitochondrial genetic variation orchestrates COPZ1 transcript heterogeneity and reveals telomere-mediated vulnerabilities in osteosarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C038.