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

Abstract

Funding information Princess Máxima Center FoundationAims: 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 D. Maroeska W. M. te Loo and Marieke J. H. Coenen have contributed equally to this work.The authors confirm that the PI for this paper is D. Maroeska W. M. te Loo and that she had direct clinical responsibility for part of the patients.

Novel Aspects of Leukemia Pharmacogenomics

“…However, information continues to be gathered from studies in different populations, and there are variants that stand out as candidates to be considered for validation as actionable variants that are recognized by the specialized Another drug that is commonly used in the treatment of leukemia is vincristine, which is associated with a risk of neuropathy. Some variants in the cytochromes p450 CYP3A4 and CYP3A5, as well as the variant CEP72 rs924607 encoding centrosomal protein 72 (78,79), have been described that produce changes in its expression and that serve as a reference for modifying drug doses. However, the results from different studies have been contradictory, which mainly concerns the CYP isoforms (80)(81)(82), and this effect is most likely related to the ancestry and genetic background of the studied populations (83).…”