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Contains fulltext : 290144.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 251722.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, 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.

Radboud University, 16 december 2022, Promotores : Noordam, C., Guchelaar (LUMC), H.J. Co-promotores : Coenen, M.J.H., Loo, D.M.W.M. te, Contains fulltext : 284845.pdf (Publisher’s version ) (Open Access), Brain tumors are the most common type of solid tumors in childhood. Some type of brain tumors need to be treated with chemotherapy, which can lead to severe side effects. It is known that one child is more sensitive to develop chemotherapy side effects than the other child, but it is unknown what causes this difference. This thesis describes studies in which the impact of differences in DNA between these patients as a cause of the differences in chemotherapy side effects. These studies, two new genes came to light in relation to hearing loss and kidney damage caused by chemotherapy (TSPAN5 and RBMS3). Also, an already discovered gene (CEP72) is studied in more detail in relation to the side effect nerve damage. By doing so, this thesis has contributed to a better understanding of the role of differences in DNA in the development of chemotherapy side effects, and a step towards prediction and prevention of these side effects.

Contains fulltext : 222069.pdf (publisher's version ) (Open Access)

Contains fulltext : 170603pub.pdf (publisher's version ) (Closed access) Contains fulltext : 170603post.pdf (postprint version ) (Open Access), AIM: This systematic review provides an overview of publications concerning pharmacogenetic research in pediatric patients with medulloblastoma and low-grade glioma. MATERIALS & METHODS: Three electronic databases searches including a manual search were performed to identify studies investigating potential interactions between germline variants and chemotherapy efficacy and toxicity. RESULTS: Out of 3570 citations, 21 studies were included. Outcomes include overall survival, progression-free survival and treatment-related adverse events (n = 5), cisplatin-induced ototoxicity (n = 13) and vincristine-induced neurotoxicity (n = 3). CONCLUSION: This review shows that the number of pharmacogenetic studies in well-defined pediatric brain tumor cohorts is poor and studies often report conflicting results. Large-scale international collaborations allowing analysis of sufficiently sized cohorts are therefore very important for the future of personalized medicine in brain tumors.