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

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.

Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients

“…The relation between sex and VIPN remains unclear [ 2 ]. Moreover, it was shown that ancestry is associated with VIPN development, with studies showing that Caucasian children are more often affected than African(-American) children [ 10 , 11 ]. It was thus hypothesized that genomic factors are associated with VIPN [ 11 ].…”

“…Moreover, it was shown that ancestry is associated with VIPN development, with studies showing that Caucasian children are more often affected than African(-American) children [ 10 , 11 ]. It was thus hypothesized that genomic factors are associated with VIPN [ 11 ]. Initially, this research focused on genomic differences between the CYP3A4 and CYP3A5 enzymes, since there was an ancestry dependent difference in the distribution of protein expression (i.e., African-American children express more CYP3A5 and Caucasian children express more CYP3A4).…”

“…CYP3A5 was associated with faster metabolization and lower exposure to VCR [ 10 , 12 , 13 , 14 , 15 , 16 ], which could possibly explain the lower rate of VIPN in African-American children. However, these results were conflicting and could not fully explain the individual differences between VIPN [ 11 ]. In 2015, a genome-wide association study (GWAS) was published that identified a single-nucleotide polymorphism (SNP) in the gene coding for the Centrosomal Protein 72 (CEP72) that was associated with VIPN development [ 5 ].…”

“…Other studies have replicated this association since then [ 17 , 18 ]. To summarize all pharmacogenomic parameters associated with VIPN, we recently performed a systematic review and meta-analysis in which we found that SNPs in transporter-, metabolism-, cytoskeleton-, and hereditary neuropathy-associated genes were associated with VIPN [ 11 ].…”

“…However, the direct effect of genetic variants on PK of VCR has not yet been studied. Understanding the association between genetic factors and PK is important, as it could lead to an individualized dosing regimen of VCR [ 9 , 11 , 19 ]. For example, children with a genetic variant associated with a higher exposure to VCR could benefit from dose reductions, whereas children who have a lower exposure might not benefit from the generally applied dose capping.…”