Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy in Children with Cancer: A Systematic Review and Meta-Analysis

SIMPLE SUMMARY: Vincristine is a drug that is part of the treatment for many children with cancer. Its main side-effect is vincristine-induced peripheral neuropathy (VIPN), which often presents as tingling, pain, and lack of strength in the hands and feet. It is not yet possible to predict which children will suffer from VIPN. In this review, we report on all genetic variations that are associated with VIPN. We found that variations in genes related to vincristine transport, cell structure, hereditary nerve disease, and genes without a previously known connection to vincristine or VIPN are related to VIPN. Variations in genes involved in vincristine breakdown are not significantly associated with VIPN. In conclusion, genetic variations affect a child’s tendency to develop VIPN. In the future, this information might be used to predict the risk of VIPN and adapt treatment on this. ABSTRACT: Vincristine-induced peripheral neuropathy (VIPN) is a debilitating side-effect of vincristine. It remains a challenge to predict which patients will suffer from VIPN. Pharmacogenomics may explain an individuals’ susceptibility to side-effects. In this systematic review and meta-analysis, we describe the influence of pharmacogenomic parameters on the development of VIPN in children with cancer. PubMed, Embase and Web of Science were searched. In total, 1597 records were identified and 21 studies were included. A random-effects meta-analysis was performed for the influence of CYP3A5 expression on the development of VIPN. Single-nucleotide polymorphisms (SNPs) in transporter-, metabolism-, cytoskeleton-, and hereditary neuropathy-associated genes and SNPs in genes previously unrelated to vincristine or neuropathy were associated with VIPN. CYP3A5 expression status was not significantly associated with VIPN. The comparison and interpretation of the results of the included studies was limited due to heterogeneity in the study population, treatment protocol and assessment methods and definitions of VIPN. Independent replication is essential to validate the clinical significance of the reported associations. Future research should aim for prospective VIPN assessment in both a discovery and a replication cohort. Ultimately, the goal would be to screen patients upfront to determine optimal vincristine dosage with regards to efficacy and risk of VIPN.