Germline susceptibility and immunometabolic pathways contributing to treatment-related neurotoxicity and neurocognitive outcomes in childhood acute lymphoblastic leukaemia (360G-Wellcome-341562_Z_25_Z)

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Treatment-related neurological toxicity remains a substantial and potentially preventable burden. Approximately 10% of children experience acute central nervous system events, and up to 40% develop long-term neurocognitive impairment which impacts functional outcomes and quality of life. This project will investigate germline susceptibility and biological mechanisms underlying neurological sequelae in childhood ALL survivors. Aim 1 will use genome-wide association studies to identify germline variants associated with acute neurotoxicity and long-term cognitive outcomes. Polygenic risk scores will be integrated with treatment and environmental exposures to develop multivariable risk prediction models. Aim 2 will apply Mendelian randomization to explore the causal role of immune, inflammatory, and metabolic biomarkers in these outcomes. Aim 3 will analyse existing MRI data from ALL survivors and matched controls to map region-specific brain vulnerabilities. A feasibility pilot study using diffusion-weighted magnetic resonance spectroscopy will characterise persistent in vivo markers of chemotherapy-related neuroinflammation. Integrated analysis of germline genetics, causal biomarker pathways, and advanced neuroimaging across international cohorts will provide insight into the factors driving individual variation in treatment-related neurological toxicity. Findings have the potential to inform risk stratification and supportive care strategies within emerging treatment protocols.