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- Title
Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients.
- Authors
van de Velde, Mirjam E.; Uittenboogaard, Aniek; Yang, Wenjian; Bonten, Erik; Cheng, Cheng; Pei, Deqing; van den Berg, Marleen H.; van der Sluis, Inge M.; van den Bos, Cor; Abbink, Floor C. H.; van den Heuvel-Eibrink, Marry M.; Segers, Heidi; Chantrain, Christophe; van der Werff ten Bosch, Jutte; Willems, Leen; Evans, William E.; Kaspers, Gertjan J. L.
- Abstract
Simple Summary: Vincristine is a type of chemotherapy that is often used in the treatment of children with cancer. The main side effect of vincristine is nerve damage. Patients experience symptoms such as tingling, pain or muscle weakness. Some children are more sensitive to vincristine than others, which may depend on variations in genes and in the breakdown of vincristine by the body. In this study, we investigated the effect of variations in genes on nerve damage due to vincristine and breakdown of vincristine by the body. We found that nine variations in seven genes were associated with nerve damage due to vincristine, whereas three variations in three genes were associated with the breakdown of vincristine by the body. It is important that future studies try to replicate these findings. Our findings help us towards the goal of tailoring vincristine treatment to each child, with optimal therapeutic effect while limiting nerve damage. Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and pharmacokinetics (PK). In this study, we identify and replicate genetic variants associated with VCR PK and VIPN. Patient samples from a randomized clinical trial studying the effect of administration duration of VCR on VIPN in 90 patients were used. PK sampling was conducted on between one and five occasions at multiple time points. A linear two-compartment model with first-order elimination was used, and targeted next-generation DNA sequencing was performed. Genotype–trait associations were analyzed using mixed-effect models or logistic regression analysis for repeated measures, or Poisson regression analysis in which the highest VIPN score per patient was included. Nine single-nucleotide polymorphisms (SNPs) in seven genes (NDRG1, GARS, FIG4, FGD4, SEPTIN9, CEP72, and ETAA1) were associated with VIPN. Furthermore, three SNPs in three genes (MTNR1B, RAB7A and SNU13) were associated with PK of VCR. In conclusion, PK of VCR and VIPN are influenced by SNPs; upfront identification of those that lead to an altered susceptibility to VIPN or VCR exposure could help individualize VCR treatment.
- Subjects
PERIPHERAL neuropathy; SEQUENCE analysis; SINGLE nucleotide polymorphisms; GENETIC polymorphisms; GENETIC variation; CANCER patients; GENOMES; LOGISTIC regression analysis; VINCRISTINE; POISSON distribution; PHARMACODYNAMICS; CHILDREN
- Publication
Cancers, 2022, Vol 14, Issue 14, pN.PAG
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers14143510