Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

Abstract

Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10^-5 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10^-4 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10^-4 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN.

Figure 1

CEP72 is significantly associated with vincristine‐induced peripheral neuropathies (VIPN) in pediatric patients with acute lymphoblastic leukemia. (a) Recessive genotype frequencies for CEP72 rs924607 differed significantly between VIPN cases and controls (P = 0.02). The TT risk genotype occurred in 16.0% of cases (VIPN grade ≥2) and 5.4% of controls (VIPN grade 0). (b) Meta‐analysis of the association of CEP72 rs924607 and VIPN confirms the role of this variant with vincristine‐related adverse effects. The gray summary diamond indicates meta‐analysis results including all studies, whereas the blue summary diamond shows the results for studies where VIPN was assessed throughout continuation therapy (i.e., excluding the Gutierrez‐Camino et al.¹² study). Genotype 95% confidence intervals (CIs) are represented for consistency across all studies, as opposed to the 90% CI that was used to determine CEP72 rs924607 replication evidence for the Canadian Pharmacogenomics Network for Drug Safety cohort in the current study.^10,13,14

Figure 2

Top absorption, distribution, metabolism, and excretion (ADME)‐vincristine‐induced peripheral neuropathies (VIPN) variant genotypes stratified by severity of the adverse event. (a) ABCC1 rs3784867 was the most significantly associated pharmacogenomic variant in the VIPN‐ADME analyses (P = 5.34 × 10⁻⁵; odds ratio (OR) = 4.9). Genotype frequency was also correlated with severity of the adverse event (P = 7.12 × 10⁻⁴). (b) SLC5A7 rs1013940 is a missense variant in a peripheral neuropathy gene that was among the most significantly associated ADME variants (P = 9.00 × 10⁻⁴; OR = 8.6). The variant was also moderately associated with VIPN grade severity (P = 0.01), with all homozygous carriers of the risk allele presenting with severe VIPN (i.e., grade 3 and 4). Because only one case of grade 4 VIPN was observed in this cohort, this patient was combined with the grade 3 group.

Figure 3

Association of TTPA‐related variation and gene expression with vincristine‐induced peripheral neuropathy (VIPN). (a) Meta‐analysis of overlapping absorption, distribution, metabolism, and excretion (ADME)‐genomewide association study (GWAS) variants in the Canadian Pharmacogenomics Network for Drug Safety (CPNDS)/St Jude Total XIIIB/COG AALL0433 cohorts identified rs10504361 as the most significantly associated variant. (b) This variant has been shown to be associated with differential expression of the TTPA gene in the tibial nerve in GTEx. (c) Imputing expression of TTPA using genome wide array data revealed that VIPN cases were predicted to have higher levels of TTPA expression compared to controls as reflected by gene‐level S‐PrediXcan Z‐scores (i.e., positive scores indicate increased expression is associated with increased risk for VIPN). CI, confidence interval; OR, odds ratio.