The pharmacogenomics of vincristine-induced neurotoxicity in paediatric cancer patients with Wilms tumor or rhabdomyosarcoma

Vincristine is one of the most effective and widely utilized antineoplastic agents. However, the clinical utility of this drug is limited by severely debilitating vincristineinduced neurotoxicities (VIN). Previous studies have associated VIN with genetic polymorphisms in genes involved in the metabolism and transportation of vincristine, including CYP3A4, CYP3A5, and ABCB1. However, the findings of such studies have not been consistently reproduced. This study hypothesizes that there are specific variants in genes involved in general drug absorption, metabolism, distribution, excretion, and toxicity (ADME-Tox) that affect the individual susceptibility to VIN in patients with Wilms tumor and rhabdomyosarcoma. Detailed clinical data was collected from 140 patients with Wilms tumor and rhabdomyosarcoma by retrospective chart review. VIN cases were characterized by type of neurotoxicity, and severity was evaluated using a validated clinical grading system for adverse events (NCI-CTCAE v4.03). A customized Illumina GoldenGate Panel was used to genotype 4,536 single nucleotide polymorphisms (SNPs) in candidate genes involved in the metabolism and transportation pathway of vincristine, as well as in genes broadly involved in ADME-Tox. None of the SNPs that were previously reported to be associated with VIN were found to be significantly associated (p-value < 0.05). With similar effect sizes, six novel genetic variants in five genes (PON1, ABCA4, ABCG1, CY51A1, SLCO1C1) were significantly associated with VIN in both tumor types. Whereas none of these genes have been previously associated with VIN or the biotransformation of vincristine, interestingly,the biological functions of the encoded proteins have been indirectly linked to nerve function, neuropathy, or neurodegenerative diseases. Therefore, I hypothesize that the genetic basis of VIN is likely polygenic and that the six genes influence individual susceptibility to VIN by affecting: nerve regeneration (PON1, PPP1R9A), and cholesterol homeostasis and remyelination (ABCA4, ABCG1, CYP51A1), as well as the metabolism of vincristine (PON1, CYP51A1) and the transportation of lipids, vincristine, metabolites, or neuroprotectants (SLCO1C1, ABCA4, ABCG1). This study adds to the literature by identifying new potential biomarkers for VIN, providing novel hypotheses for the mechanisms underlying VIN susceptibility, and is a point of origin for replication studies.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat