Genomic variations associated with risk and protection against vincristine-induced peripheral neuropathy in pediatric cancer patients

Abstract

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10^-8) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006).

Fig. 1. Manhattan plot of the vincristine-induced peripheral neuropathy GWAS summary statistics.

Manhattan plot highlighting the GWAS-nominated loci associated with the risk of vincristine-induced neuropathy. Each point represents the log p-value at each genomic position from Chromosome 1 to Chromosome 22. The genome-wide significance threshold was set at 5 × 10⁻⁸ (black dashed line).

Fig. 2. Vincristine neuropathy pathways associated with genes nominated by GWAS.

a Vincristine-induced peripheral neuropathy GWAS pathways nominated by gene-set enrichment analysis using WebGestalt (http://www.webgestalt.org/) in cellular components, biological processes, and molecular functions. The bars represent the Bonferroni corrected p-values, and the red dashed line indicates a significance threshold of p = 0.05. b Key GWAS-significant loci across different pathophysiology, where a significant overlap is observed between the gene sets involved in different pathways, suggesting that an interaction between these pathways contributes to the overall risk of vincristine peripheral neuropathy.

Fig. 3. Vincristine-induced peripheral neuropathy-related pathophysiology.

Schematic overview of the key GWAS-significant loci across different vincristine peripheral neuropathy-related pathophysiology. a VTI1A regulates neuronal development, Golgi secretion, and extracellular transport of neurons^,; NRG3 plays a role in intracellular signal transduction and nervous system development; Actin provides structural support for neurons and regulates neuronal shape. b MCM3AP is implicated in axonal and demyelinating CMT neuropathy^,; ZFAND proteins regulate the clearance of aberrant stress granules (SGs) via the ubiquitin/proteasome system, preventing stress vulnerability in motoneurons and CMT caused by aberrant-SGs^–,; Neuregulin interacts with ErbB to promote myelination of peripheral axons and motor axon maturation^–. c Actin filaments regulate axon growth, guidance, and active axonal transport^,; ARHGAP5 mediates cytoskeleton changes and promotes actin polymerization through regulating Rho GTPases; FBN2 provides mechanical and functional support to peripheral nerves and is implicated in early-onset neuropathies^,–. d VTI1A regulates the fusion of synaptic vesicles with the presynaptic membrane via interacting with t-SNAREs complex proteins^,,; Actinin regulates neurotransmitter release from presynaptic terminals and modulates synaptic plasticity via activating CaMKII in post-synapse neurons^,–; NRG3 promotes excitatory synapse formation and plasticity, and modulates synaptic transmission through activating ErbB4^,,; LRRTM3 induces synapse development and differentiation through interacting with pre-synapse neurexins^,–. The figure was created with BioRender.com and Adobe Illustrator^® Creative Cloud.