ODC1 inhibition and neuroblastoma: A drug-target Mendelian randomization, eQTL colocalization and drug sensitivity study.

OBJECTIVE: This study aimed to investigate the potential causal relationship between the genetically predicted effects of ornithine decarboxylase (ODC) inhibitors, such as difluoromethylornithine (DFMO), and the risk of neuroblastoma (NB) using a Mendelian randomization (MR) and drug sensitivity prediction approach. METHODS: Genetic variants associated with ODC and NB were selected from GWAS summary data. Statistical methods, including inverse-variance weighted (IVW), weighted median and MR-Egger, were employed to estimate causal effects. Colocalization analysis was performed to investigate the biological mechanisms behind drug target gene ODC1 inhibition and NB. We employed CellHit to perform robust prediction of DFMO drug sensitivity in NB patient samples. RESULTS: No significant colocalization was observed between ODC1 eQTLs and NB (PP.H4.abf = 0.15). Inhibition of ODC1 does not appear to genetically influence the risk of common NB. Drug sensitivity analysis revealed that, across the full cohort, the predicted log-fold change (preLFC) of DFMO response showed no significant correlation with ODC1 expression levels. However, subgroup analysis based on MYCN status demonstrated a significant negative correlation between preLFC and ODC1 expression specifically in the MYCN non-amplified subgroup. CONCLUSIONS: Drug sensitivity analysis suggests that ODC1 may serve as a valuable therapeutic target in high-risk NB patients without MYCN amplification, with DFMO emerging as a potential candidate drug for this subgroup. ODC1 is not involved in the initiation of NB, but it plays an important role in tumour progression and treatment response in a subset of patients.