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. 2022 Jul 19;14(14):3510.
doi: 10.3390/cancers14143510.

Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients

Mirjam E van de Velde  1   2 , Aniek Uittenboogaard  1   3 , Wenjian Yang  2 , Erik Bonten  2 , Cheng Cheng  4 , Deqing Pei  4 , Marleen H van den Berg  1 , Inge M van der Sluis  3 , Cor van den Bos  3   5 , Floor C H Abbink  5 , Marry M van den Heuvel-Eibrink  3 , Heidi Segers  6 , Christophe Chantrain  7 , Jutte van der Werff Ten Bosch  8 , Leen Willems  9 , William E Evans  2 , Gertjan J L Kaspers  1   3
Affiliations

Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients

Mirjam E van de Velde et al. Cancers (Basel). .

Abstract

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.

Keywords: DNA; area under the curve; cancer; children; maximum concentration; neurotoxicity; single-nucleotide polymorphism; toxicity; vincristine; whole-exome sequencing.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
(A) Association between a SNP in SNU13 and vincristine (VCR) pharmacokinetics (PK). (B) Association between a SNP in RAB7A and VCR PK. (C) Association between a SNP in MTNR1 and VCR PK. PK samples were collected in 35 patients on maximum 70 occasions; every occasion per patient is shown. The number in the boxplot indicates the number of observations per genotype. The p-value was derived from mixed-effect linear regression for repeated measures, where the genotype was considered to be a categorical variable. SNU13: Small Nuclear Ribonucleoprotein 13, RAB7A: RAS-related protein 7A, MTNR1B: Melatonin Receptor 1B.
Figure 2
Figure 2
(A) Association between a SNP in NRDG1 and total Common Toxicity Criteria of Adverse Events (CTCAE) score. (B) Association between a SNP in GARS and total CTCAE score. (C) Association between a SNP in FGD4 and pediatric-modified Total Neuropathy Score (ped-mTNS). (D) Association between a SNP in CEP72 and ped-mTNS score. VIPN measurements were performed 1–5 times in 85 patients. Every VIPN measurement per patient across the time points is shown. The number in the boxplot indicates the number of observations per genotype. The p-value was derived from Poisson regression analysis for repeated measures, where the genotype was considered to be a categorical variable. NRDG1: N-Myc Downstream Regulated 1, GARS: Glycyl tRNA Synthetase, FGD4: FYVE, RhoGEF and PH Domain Containing 4, CEP72: Centrosomal Protein 72.
Figure 3
Figure 3
(A) Association between a SNP in GARS and dichotomized (yes/no) VIPN scores according to the CTCAE score. (B) Association between a SNP in ETAA1 and dichotomized (yes/no) VIPN scores according to the CTCAE score. VIPN measurements were performed 1–5 times in 85 patients. Every VIPN measurement per patient across the time points is shown. The number in the boxplot indicates the number of observations per genotype. A cut-off value of a CTCAE score of ≥2 was considered to be VIPN. The p-value was derived from mixed-effect logistic regression for repeated measures. For GARS, genotype was considered to be a categorical variable, whereas for ETAA1, genotype was considered to be an ordinal variable. ETAA1: Ewing’s tumor-associated antigen 1.
Figure 4
Figure 4
Schematic overview of the significant associations between genetic variations and VCR PK and VIPN. Figure created with Biorender.com.
See this image and copyright information in PMC

References

    1. Gidding C.E., Kellie S.J., Kamps W.A., de Graaf S.S. Vincristine revisited. Crit. Rev. Oncol. Hematol. 1999;29:267–287. doi: 10.1016/S1040-8428(98)00023-7. - DOI - PubMed
    1. Van de Velde M.E., Kaspers G.L., Abbink F.C.H., Wilhelm A.J., Ket J.C.F., van den Berg M.H. Vincristine-induced peripheral neuropathy in children with cancer: A systematic review. Crit. Rev. Oncol. Hematol. 2017;114:114–130. doi: 10.1016/j.critrevonc.2017.04.004. - DOI - PubMed
    1. Van de Velde M.E., Van den Berg M.H., Kaspers G.J.L., Abbink F.C.H., Twisk J.W.R., van der Sluis I.M., van den Bos C., van den Heuvel-Eibrink M.M., Segers H., Chantrain C., et al. The association between vincristine-induced peripheral neuropathy and health-related quality of life in children with cancer. Cancer Med. 2021;10:8172–8181. doi: 10.1002/cam4.4289. - DOI - PMC - PubMed
    1. Tay C.G., Lee V.W.M., Ong L.C., Goh K.J., Ariffin H., Fong C.Y. Vincristine-induced peripheral neuropathy in survivors of childhood acute lymphoblastic leukaemia. Pediatric Blood Cancer. 2017;64:e26471. doi: 10.1002/pbc.26471. - DOI - PubMed
    1. Diouf B., Crews K.R., Lew G., Pei D., Cheng C., Bao J., Zheng J.J., Yang W., Fan Y., Wheeler H.E., et al. Association of an Inherited Genetic Variant With Vincristine-Related Peripheral Neuropathy in Children With Acute Lymphoblastic Leukemia. JAMA. 2015;313:815–823. doi: 10.1001/jama.2015.0894. - DOI - PMC - PubMed

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