Background and importance High-dose methotrexate (HDMTX) is the most widely used systemic treatment in paediatric cancer due to its high effectiveness, easy administration and low cost.The great interindividual variability in relation to toxicities derived from HDMTX treatment may be caused by genetic variants in genes involved in the metabolism and transport of methotrexate (MTX). The study of these variants involved in the MTX pathway could help to predict the toxicity profile associated with HDMTX treatment.
Aim and objectives To evaluate the influence of polymorphisms in MTR, MTRR, MTHFR, MTHFD1, ATIC and SLCO1B1 genes on the development of toxicity during treatment with HDMTX in paediatric oncology patients.
Material and methods A multicentre retrospective study was carried out during 2021 in two third-level hospitals. The study was been approved by the Ethics and Clinical Research Committee of the Hospital with the prior informed consent of the patients for their inclusion in the study.
Data: DNA extraction was performed from swabs with saliva samples using a QIAamp DNA Mini Kit. The polymorphisms were studied by via OpenArray by QuantStudio 12K Flex System using the ‘TaqMan PGx Express’ array. Clinical–pathological characteristics and toxicities were obtained by reviewing the clinical history of the patients. Relation between pathological–clinical features, polymorphisms and toxicities were studied using bivariate analysis with Software R 4.1.1 version.
Results A total of 64 patients aged between 0–14 years which were treated with HDMTX in the last 10 years were studied. Patients carrying the allele G of MTR rs3768142 variant had a higher probability of presenting hepatotoxicity (p=0.007, OR 4,25, IC95% 1.45 to 12.42), gastrotoxicity (p=0.00001, OR 9.18, IC95% 2.96 to 29.46) and haemotoxicity (p=0.0195,OR 9.5, IC95% 1.04 to 86.97). The analysis showed that patients with the allele G of MTRR rs3768142 variant had a higher incidence of hepatotoxicity (p=0.05, OR 3.1, IC95% 0.95 to 10.11). In addition, the presence of the allele A in MTHFR rs1801133 gene polymorphism indicated the presence of haemotoxicity (p=0.037, OR 5.73, IC95% 9.95 to 34.55).
Conclusion and relevance The results obtained in this study suggest that patients who present some of the polymorphisms indicated above may present a higher rate of toxicity in paediatric oncology patients with HDMTX treatment. This would allow us in the future to carry out an individualised therapy that provides greater efficacy and less toxicity associated with the treatment.
Conflict of Interest No conflict of interest
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