Pharmacogenomic study of vincristine-induced peripheral neuropathy in patients with pediatric cancers
department or school: Medicine, Faculty of
department or school: Medical Genetics, Department of
data provider: DSpace
degree campus: UBCV
creator: Mufti, Kheireddin
issued: 2025-05-20T18:19:00Z
issued: 2025
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: 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: 0.124â0.602; p<0.001). A follow-up pathway analysis revealed involvement of four key pathways, including nerve development, nerve myelination, neuronal transmission, and cytoskeleton/microfibril f…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/91165
note: PHARMACOGENOMIC STUDY OF VINCRISTINE-INDUCED PERIPHERAL NEUROPATHY IN PATIENTS WITH PEDIATRIC CANCERS by Kheireddin Mufti B.Pharm., University of Aleppo, 2016 M.Sc., McGill University, 2020 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) May 2025 © Kheireddin Mufti, 2025ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Pharmacogenomic study of vincristine-induced peripheral neuropathy in patients with pediatric cancers Examining Committee: Bruce Carleton, Professor, Department of Pediatrics, UBC Supervisor Jan Friedman, Professor, Department of Medical Genetics, UBC Supervisory Committee Member Steven Miller, Professor, Department of Pediatrics, UBC University Examiner Michael Cox, Professor, Department of Experimental Medicine, UBC University Examiner Additional Supervisory Committee Members: Colin Ross, Professor, Department of Medical Genetics, UBC Co-supervisor S. Rod Rassekh, Clinical Associate Professor, Department of Pediatrics, UBC Supervisory Committee Member William Gibson, Professor, Department of Medical Genetics, UBC Supervisory Committee Member submitted by Kheireddin Mufti in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Medical Genetics iii Abstract 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 vincristin…
has type: Thesis/Dissertation
date issued: 2025-11
is shown at: 10.14288/1.0448919
language: eng
degree discipline: Medical Genetics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Carleton, Bruce C.
contributor: Ross, Colin J.
type: Text
identifier URI: http://hdl.handle.net/2429/91165