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Meta-Analysis
. 2022 Jul;88(7):3463-3473.
doi: 10.1111/bcp.15267. Epub 2022 Mar 24.

Contribution of common and rare genetic variants in CEP72 on vincristine-induced peripheral neuropathy in brain tumour patients

Marije J Klumpers  1 , Annouk C A M Brand  2 , Marina Hakobjan  2 , Giovanna Gattuso  3 , Elisabetta Schiavello  3 , Monica Terenziani  3 , Maura Massimino  3 , Corrie E M Gidding  4 , Henk-Jan Guchelaar  5 , D Maroeska W M Te Loo  6 , Marieke J H Coenen  7
Affiliations
Meta-Analysis

Contribution of common and rare genetic variants in CEP72 on vincristine-induced peripheral neuropathy in brain tumour patients

Marije J Klumpers et al. Br J Clin Pharmacol. 2022 Jul.

Abstract

Aims: Studies implicated a role for a genetic variant in CEP72 in vincristine-induced peripheral neuropathy. This study aims to evaluate this association in a cohort of brain tumour patients, to perform a cross-disease meta-analysis and explore the protein-coding region of CEP72.

Methods: In total, 104 vincristine-treated brain tumour patients were genotyped for CEP72 rs924607, and sequenced for the protein-coding region. Data regarding patient and treatment characteristics, and peripheral neuropathy, were collected. Logistic regression and meta-analysis were performed for rs924607 replication. A weighted burden analysis was applied to evaluate impact of overall genetic variation in CEP72.

Results: Analysis of 24 cases and 80 controls did not show a significant association between CEP72 rs924607 and neuropathy (odds ratio, OR [95% confidence interval, CI] 2.076 [0.359-11.989], P = .414). When combined with 8 cohorts (1095 cancer patients), a significant increase in risk for neuropathy was found for patients with a TT genotype (OR [95% CI] 2.15 [1.35-3.43], P = .001). Additionally, a missense variant (rs12522955) was significantly associated (OR [95% CI] 2.3 [1.2-4.4], P = .041) and patients with severe neuropathy carried more impactful variants in CEP72 coding regions (P = .039).

Conclusion: The association of CEP72 rs924607 in vincristine-induced neuropathy was not confirmed in a cohort of brain tumour patients, but did contribute to its suggested effect when combined in a cross-disease meta-analysis. The importance of other genetic variations in CEP72 on vincristine-induced neuropathy was demonstrated. This study contributes to evidence of the importance of genetic variants in CEP72 in development of vincristine-induced toxicity, and provides guidance for future prospective studies.

Keywords: CEP72; brain tumours; neuropathy; pharmacogenetics; vincristine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Percentage of patients who developed vincristine‐induced peripheral neuropathy (VIPN; grade 2 or higher, dark blue bars), and who did not develop VIPN (grade 0, light blue bars), with on the x‐axis CEP72 rs924607 genotyping under the assumption of a recessive genetic model (CC/CT vs. TT). The number within de bar indicates the number of patients. No statistically significant difference was observed in the frequency of the TT genotype between VIPN cases and controls. Multivariate logistic regression analysis (with treatment protocol and age at diagnosis included as covariates) did not show a statistically significant association (CC/CT genotype vs. TT genotype; OR 2.076 [95% CI 0.359–11.989] P = .414)
FIGURE 2
FIGURE 2
Meta‐analysis (random effects model) of nine cohorts investigating the association between CEP72 rs924607 and risk for development of vincristine‐induced peripheral neuropathy (VIPN), resulting in a statistically significant effect of TT genotype on risk of development of VIPN
FIGURE 3
FIGURE 3
Weighted genotype analysis of CEP72 and vincristine‐induced peripheral neuropathy (VIPN). The top of the bar chart represents the mean weighted genotype score in each group and the whiskers show the corresponding standard deviation. A statistically significant difference (P = .039) was observed between the different groups
See this image and copyright information in PMC

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