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

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<sup>-8</sup>) 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).

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Publication Details

Journal
npj Genomic Medicine
Published
2024-11-05
DOI
https://doi.org/10.1038/s41525-024-00443-7
Citations
5
Primary Topic
Cancer Treatment and Pharmacology
Type
article
Field-Weighted Citation Impact
1.41

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

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

Kheireddin Mufti, Kerry B. Goralski, Geoff D.E. Cuvelier, Thai Hoa Tran, Michelle Higginson, Tamorah Lewis, Erika N. Scott, Miguel Córdova‐Delgado, Bishal Gyawali, Gabriella Groeneweg, Maja Krajinović, Denis Lebel, Paul Craig Nathan, Bruce Carleton, Colin J.D. Ross, Lucie Pecheux, Jessica M. Lovnicki, Fudan Miao, Awatif M. Abuzgaia, Derek Yau, Donna L. Johnston, Zara Forbrigger, Thaïna-Rafi Jean-Baptiste, Ketan Prasad Kulkarni, A. Perreault, Kathy Li, Jessica N. Trueman, Shahrad R. Rassekh, Gregory M.T. Guilcher, Sara Khalaj, Catrina M. Loucks, Michael Rieder, Jean‐François Bussières, Michelle Staub, Wan‐Chun Chang, Geert ‘t Jong, Matheus Sampaio Ibrahim, H. Ghimire, Kathleen Felton, Forough Abbasi, Gesche Riabowol
article en
5 citations

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<sup>-8</sup>) 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).

npj Genomic MedicineVol. 9(1)
University of British Columbia (CA), Children's Hospital of Eastern Ontario (CA), Izaak Walton Killam Health Centre (CA), London Health Sciences Centre (CA), Hospital for Sick Children (CA), Alberta Children's Hospital (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), Health Sciences Centre (CA), BC Children's Hospital (CA), Stollery Children's Hospital (CA)
International Association for the Study of Pain, Genome Canada, Children's Hospital Foundation, BC Children’s Hospital Foundation, BC Children's Hospital, Michael Smith Health Research BC, Genome British Columbia, Provincial Health Services Authority, University of British Columbia, Centers for Disease Control and Prevention, Health Canada, Canadian Institutes of Health Research
Openalex Percentile: Top 15%
Cancer Treatment and Pharmacology
1.41
DOIOpen Access PDFOpenAlex
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