001: Genomic Risk Factors of Vincristine-Induced Peripheral Neuropathy

Statement of Purpose: Vincristine-induced peripheral neuropathy (VIPN) is a debilitating toxicity of treatment that can reduce both quality of life and survival. Previous studies have identified genetic variations associated with VIPN risk; however, their clinical relevance has been limited due to small sample sizes and unclear clinical phenotypes. This study aims to identify pharmacogenomic risk factors of VIPN in a large and well-characterized cohort of patients with pediatric cancers.

Description of Methods & Materials: A nested case-control study of 1,100 pediatric cancer patients from ten Canadian academic health centres through the Canadian Pharmacogenomics Network for Drug Safety (CPNDS). VIPN was defined according to the Common Terminology Criteria for Adverse Effects (CTCAE v5.0). VIPN cases (CTCAE Grade ≥ 2; n=550) and controls (CTCAE Grade 0; n=550) were matched by vincristine cumulative exposure and genetic ancestry. Patients with mild VIPN (CTCAE Grade 1; n=155) were excluded to ensure case/control phenotypic discrimination. A genome-wide association study (GWAS) was performed using genotype data generated with custom Illumina Infinium® Global Screening Array (GSA v2.0) and supplemented with genotype imputation.

Data & Results: The GWAS analysis revealed significant associations (p < 5.0x10-8) between VIPN risk and genetic variations in several genes, including MCM3AP that strongly increases VIPN risk by 6-fold (OR=6.3 [95%CI:2.9-12.5], p=3.1x10-8), NRG3 (OR=0.15 [95%CI:0.07-0.33] p=3.2x10-8), FBN2 (OR=0.36 [95%CI:0.25-0.50], p=4.3x10-8) and LRRTM3 (OR=0.14 [95%CI:0.06-0.33], p=4.8x10-8,) significantly decrease VIPN risk by 3-7 fold. MCM3AP gene causes recessive forms of Charcot-Marie-Tooth disease, a common disorder that results in peripheral nerve demyelination, while NRG3 and FBN2 contribute to peripheral nerve myelination, and LRRTM3 regulates excitatory synapse development, which is crucial for normal neuronal transmission.

Interpretation, Conclusion or Significance: Genetic variations within genes related to heritable peripheral neuropathy (MCM3AP), nerve myelination (NRG3, FBN2) and synaptic assembly (LRRTM3) play an essential role in the overall susceptibility of VIPN.

Disclosures: