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Mufti, Kheireddin

University of British Columbia

Vincristine is a cornerstone chemotherapeutic agent widely used for the treatment of various pediatric cancers. However, its clinical utility is often compromised by the occurrence of vincristine-induced peripheral neuropathy, which significantly impacts quality of life due to pain and disability, and may require dose reduction, treatment delays or discontinuation that increases the risk of relapse. While several studies have identified genetic factors that are associated with vincristine peripheral neuropathy risk, these variants do not fully explain the variability in the risk of this reaction, and the clinical relevance of many variants remains unclear. As result, there are currently no established predictors of peripheral neuropathy risk prior to the start of vincristine treatment. This dissertation aims therefore to identify, and validate, novel genomic markers of vincristine-induced neuropathy in pediatric cancer patients. A systematic review of existing genetic associations with vincristine-induced peripheral neuropathy was performed and demonstrated that variations in genes implicated in vincristine pharmacokinetics, pharmacodynamics, and neuropathy-related pathways are associated with vincristine-induced peripheral neuropathy susceptibility. Among these, the CEP72 rs924607 gene variant emerged as the most robustly supported variant influencing neuropathy risk. I subsequently conducted a genome-wide association study uncovering 13 novel genomic variants significantly associated with vincristine neuropathy risk or protection. Of these, I successfully validated two variants an independent replication cohort. Notably, patients carrying protective variants in both NRG3 and ACTN1 genes exhibited a substantial reduction in neuropathy incidence over time (HR=0.36, 95% CI: 0.124–0.602; p<0.001). A follow-up pathway analysis revealed involvement of four key pathways, including nerve development, nerve myelination, neuronal transmission, and cytoskeleton/microfibril functions-related pathways. Finally, a targeted analysis of the CEP72 rs924607 variant was conducted in a subset group of patients revealing its association with significant increase in neuropathy risk following prolonged vincristine therapy (OR=3.457, 95% CI: 1.143-10.45; p=0.028). These findings present potential actionable genomic markers of vincristine-induced neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. Overall, the work discussed in this dissertation contributes to expanding the existing vincristine pharmacogenomic literature and provides needed insights into the underlying pathology of vincristine-induced peripheral neuropathy reaction in pediatric oncology patients.

Text

2025-05-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/91165

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/