Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Genomic Analysis
2.3. Pharmacokinetic Analysis
2.4. Assessment of VIPN
2.5. Statistical Analysis
3. Results
3.1. Study Population
3.2. Genomic Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patients (Total Cohort) (n = 90) | Patients (PK Cohort) (n = 35) | Patients (DNA Cohort) (n = 85) | |
---|---|---|---|
Age in years (mean, SD) | 9.17 (5.15) | 10.06 (5.60) | 8.95 (5.00) |
Ancestry (n, %) | |||
European | 73 (81.11) | 30 (85.71) | 69 (81.18) |
Non-European | 17 (18.89) | 5 (14.29) | 16 (18.82) |
Sex (n, %) | |||
Female | 40 (44.44) | 19 (54.29) | 37 (43.53) |
Male | 50 (55.56) | 16 (45.71) | 48 (56.47) |
Diagnosis (n, %) | |||
ALL | 58 (64.44) | 26 (74.29) | 54 (63.53) |
Hodgkin | 18 (20.0) | 6 (17.14) | 18 (21.18) |
Medulloblastoma | 2 (2.22) | 1 (2.86) | 2 (2.35) |
LGG | 2 (2.22) | 1 (2.86) | 2 (2.35) |
Wilms tumor | 8 (8.89) | 1 (2.86) | 7 (8.24) |
RMS | 2 (2.22) | 0 (0) | 2 (2.25) |
Mean (SD) cumulative VCR dose per m2 | 7.41 (7.99) | 13.25 (9.36) | 13.91 (9.23) |
Mean (SD) AUC ((ng·hr)/mL) | N.A. | 41.78 (14.32) | N.A. |
Mean (SD) VCR Cmax (ng/mL) | N.A. | 57.44 (31.82) | N.A. |
Median (IQR) total CTCAE score | 1.00 (0.00–2.00) | 1.00 (0.00–3.00) | 1.00 (0.00–2.00) |
Median (IQR) total ped-mTNS score * | 4.00 (1.00–8.00) | 4.00 (1.00–8.25) | 4.00 (1.00–8.50) |
Patients with VIPN according to CTCAE (%) | 40 (44.4) | 16 (45.71) | 40 (47.06) |
Outcomes per SNP | Effect Size | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Variant Heterozygous vs. Wild-Type | Variant Homozygous vs. Wild-Type | |||||||||
PK Outcomes | SNP | Wild-Type (n of Patients) | Variant Heterozygous Genotype (n of Patients) | Variant Homozygous Genotype (n of Patients) | p-Value | Regression Coefficient (95% CI) | ||||
Gene | RS-Code | Mutation | Consequence | |||||||
AUC | MTNR1B * | rs8192552 | G > A | Missense NMD transcript variant | G/G (28) | G/A (2) | A/A (0) | 0.0032 | 20.42 (8.0–32.8) | N.A. |
RAB7A * | rs4548 | C > T | Synonymous (intron) | C/C (28) | C/T (2) | T/T (0) | 0.0011 | 23.54 (10.9–36.2) | N.A. | |
Cmax | SNU13 * | rs6519270 | A > C | Non-coding transcript variant (intron) | A/A (23) | A/C (8) | C/C (1) | 0.0029 | 26.72 (7.4–46.0) | 69.55 (23.0, 116.1) |
VIPN Outcomes | SNP | Wild-Type (n of Patients) | Variant Heterozygous Genotype (n of Patients) | Variant Homozygous Genotype (n of Patients) | p-Value | Ratio of Mean (95% CI) | ||||
Gene | RS-Code | Mutation | Consequence | |||||||
Total CTCAE | NDRG1 * | rs2272653 | G > A | Splice region variant (intron) | G/G (34) | G/A (28) | A/A (19) | <0.0001 | 0.84 (0.73–0.96) | 0.49 (0.40–0.60) |
GARS * | rs1049402 | G > C | Missense transcription factor binding site variant | G/G (43) | G/C (32) | C/C (6) | 0.0013 | 0.71 (0.62–0.82) | 0.47 (0.34–0.64) | |
Total ped-mTNS | FIG4 * | rs9885672 | T > C | Missense UTR variant of the 5′ UTR | T/T (40) | T/C (19) | T/T (0) | <0.0001 | 1.44 (1.30–1.59) | N.A. |
FIG4 * | rs10659 | G > A | UTR variant of the 3′ UTR | G/G (53) | G/A (6) | G/G (0) | <0.0001 | 1.53 (1.34–1.75) | N.A. | |
FGD4 * | rs12823621 | G > A | Splice region variant (intron) | G/G (45) | G/A (13) | A/A (1) | <0.0001 | 1.43 (1.27–1.60) | 1.88 (1.36–2.59) | |
FGD4 * | rs73083501 | C > T | NMD transcript variant (intron) | C/C (39) | C/T (18) | T/T (2) | <0.0001 | 0.86 (0.76–0.97) | 0.46 (0.32–0.68) | |
SEPTIN9 * | rs11650934 | C > G | UTR variant of the 5′ UTR | C/C (41) | C/G (17) | G/G (1) | <0.0001 | 0.62 (0.54–0.71) | 0.81 (0.48–1.38) | |
CEP72 * | rs71585289 | C > G | Upstream gene variant (intron) | C/C (27) | C/G (25) | G/G (6) | <0.0001 | 0.84 (0.75–0.93) | 0.53 (0.43–0.66) | |
ETAA1 * | rs35777125 | G > A | Non-coding transcript variant (intron) | G/G (43) | G/A (15) | A/A (1) | 0.0007 | 0.9 1 (0.82–1.02) | 0.36 (0.19–0.70) | |
Dichotomized VIPN Outcomes | SNP | Genotype (n of Patients) | VIPN + (n of Observations) | VIPN − (n of Observations) | p-Value | Odds Ratio (95% CI) | ||||
Gene | RS-Code | Mutation | Consequence | |||||||
VIPN (yes/no) according to CTCAE | GARS * | rs1049402 | G > C | Missense transcription factor binding site variant | G/G (43) | 98 | 49 | 0.0107 | 0.52 (0.28–0.99) | 0.18 (0.03–0.92) |
G/C (32) | 48 | 68 | ||||||||
C/C (6) | 6 | 17 | ||||||||
ETAA1 ** | rs35777125 | G > A | Non-coding transcript variant (intron) | G/G (62) | 131 | 88 | 0.0467 | 0.31 (0.16–0.57) | ||
G/A (18) | 21 | 43 | ||||||||
A/A (1) | 0 | 3 |
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van de Velde, M.E.; Uittenboogaard, A.; Yang, W.; Bonten, E.; Cheng, C.; Pei, D.; van den Berg, M.H.; van der Sluis, I.M.; van den Bos, C.; Abbink, F.C.H.; et al. Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients. Cancers 2022, 14, 3510. https://doi.org/10.3390/cancers14143510
van de Velde ME, Uittenboogaard A, Yang W, Bonten E, Cheng C, Pei D, van den Berg MH, van der Sluis IM, van den Bos C, Abbink FCH, et al. Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients. Cancers. 2022; 14(14):3510. https://doi.org/10.3390/cancers14143510
Chicago/Turabian Stylevan de Velde, Mirjam E., Aniek Uittenboogaard, Wenjian Yang, Erik Bonten, Cheng Cheng, Deqing Pei, Marleen H. van den Berg, Inge M. van der Sluis, Cor van den Bos, Floor C. H. Abbink, and et al. 2022. "Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients" Cancers 14, no. 14: 3510. https://doi.org/10.3390/cancers14143510