High-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify determinants of methotrexate-induced toxicities in osteosarcoma patients by investigating the relation between drug plasma levels, methotrexate-induced toxicities, and germline variants in genes related to drug absorption, distribution, metabolism, and elimination. A cohort of 114 osteosarcoma patients was genotyped for 1,931 variants in 231 genes using the Drug Metabolism Enzymes and Transporters Plus array. Methotrexate plasma levels and laboratory measurements during and after high-dose methotrexate treatment concerning renal function, liver damage, and myelopoiesis to reflect toxicity outcomes were obtained. One hundred and thirteen patients and a subset of 545 variants in 176 genes passed quality control checks. Methotrexate plasma levels showed associations with creatinine, alanine aminotransferase, and hemoglobin. Genetic variant rs3736599 in the 5’-untranslated region of SULT1E1 was associated with lower 48 hour methotrexate plasma levels [coef -0.313 (95% CI -0.459 – -0.167); p = 2.60 × 10 -5 ]. Association with methotrexate-induced decreased thrombocyte counts was found for two intronic variants in CYP2B6 {rs4803418 [coef -0.187 (95% CI -0.275 – -0.099); p = 3.04 × 10 -5 ] and rs4803419 [coef -0.186 (95% CI -0.278 – -0.093); p = 8.80 × 10 -5 ]}. An association with increased thrombocyte counts was identified for the intronic variant rs4808326 in CYP4F8 [coef 0.193 (95% CI 0.099 – 0.287); p = 6.02 × 10 -5 ]. Moreover, a secondary analysis with a binary approach using CTCAE toxicity criteria resulted in a nominal significant associations (p < 0.05) for two out of three variants (rs4803418 and rs4808326). This is the first study to identify genetic variants in SULT1E1, CYP2B6 , and CYP4F8 to be associated with methotrexate pharmacokinetics and toxicities. Validation of these variants in an independent cohort and further functional investigation of variants in the identified genes is needed to determine if and how they affect methotrexate plasma levels and the development of methotrexate-induced toxicities.

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.

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.

Nephrotoxicity is a common and dose-limiting side effect of platinum compounds, which often manifests as acute kidney injury or hypomagnesemia. This study aimed to investigate the genetic risk loci for platinum-induced nephrotoxicity. Platinum-treated brain tumor and head–neck tumor patients were genotyped with genome-wide coverage. The data regarding the patient and treatment characteristics and the laboratory results reflecting the nephrotoxicity during and after the platinum treatment were collected from the medical records. Linear and logistic regression analyses were performed to investigate the associations between the genetic variants and the acute kidney injury and hypomagnesemia phenotypes. A cohort of 195 platinum-treated patients was included, and 9,799,032 DNA variants passed the quality control. An association was identified between RBMS3 rs10663797 and acute kidney injury (coefficient −0.10 (95% confidence interval −0.13–−0.06), p-value 2.72 × 10−8). The patients who carried an AC deletion at this locus had statistically significantly lower glomerular filtration rates after platinum treatment. Previously reported associations, such as BACH2 rs4388268, could not be replicated in this study’s cohort. No statistically significant associations were identified for platinum-induced hypomagnesemia. The genetic variant in RBMS3 was not previously linked to nephrotoxicity or related traits. The validation of this study’s results in independent cohorts is needed to confirm this novel association.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value &lt;10−5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5–2.7), p-value 5.0 × 10−7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.