Admixture Mapping Reveals Candidate Regions for Methotrexate Neurotoxicity Susceptibility: A Reducing Disparities in...

Neurotoxicity is a rare, often dose-limiting adverse effect of methotrexate (MTX) therapy that disproportionally affects Latino children. Factors contributing to the observed disparity are not well understood. This study leveraged admixture mapping to identify genetic regions associated with MTX-related neurotoxicity susceptibility among Latino children undergoing therapy for pediatric acute lymphoblastic leukemia (ALL).

The study cohort was composed of 429 self-identifying Latino children diagnosed with ALL (2005-2019) between the ages of 2 and 20 years treated at one of six US pediatric cancer treatment centers. MTX-related neurotoxicity was defined as neurologic episodes (e.g., seizures, stroke-like symptoms, altered mental status, and tremors) occurring within 21 days of intravenous (IV) and/or intrathecal (IT) MTX that were documented by magnetic resonance imaging (MRI) abnormalities and/or clinical symptoms. Among the 429 patients, we identified 46 (10.7%) Latino children with neurotoxicity. Admixture mapping was used to identify local genomic regions that are associated with the risk of MTX-related neurotoxicity among Latino children with ALL.

Ultimately, this study identified 11 genomic regions carrying suggestive associations with MTX-neurotoxicity risk among Latino children with ALL. Review of biological plausibility of the loci within these regions revealed associations with areas of the brain or downstream regulatory functions. Results from this study may guide future work to further interrogate these regions through fine-mapping to identify genetic variants associated with increased risk of MTX-related neurotoxicity among Latino children with ALL.