Background Genetic-polymorphisms in thiopurine-methyltransferase (TPMT) and Nudix-hydrolase15 (NUDT15) have been related to higher risk of toxicity associated with administration of 6-mercaptopurine(6-MP).
Purpose To describe the implementation of polymorphisms determination in TPMT and NUDT15 in paediatric patients by a simple and economic method.
Material and methods A multi-centre, prospective, observational study with a expected duration of 32 months was carried out. Participants were patients younger than 18 years who received treatment with 6-MP. Single nucleotide polymorphisms (SNPs) analysed were: TPMT (rs1800462;rs1800462; rs1800460;rs1142345 and rs1800584) and NUDT15 (rs116855232;rs147390019;rs554405994 and rs186364861).
DNAg extraction was carried out using the Ramos et al. method and genotyping was done using PCR and subsequent DNA sequencing. The study was approved by the hospital’s Ethical Committee (CEIC).
Legal guardians were requested to sign an informed consent form prior to inclusion.
Results During the first 8 months, nine patients were included, with an average age of 3.5 (1–18)and 62.5% of them were females. Six of the included patients (66.6%) were diagnosed with acute lymphoblastic leukaemia, two with non-Hodgkin’s lymphoma (22.2%) and one with acute myeloid leukaemia.
Eighty-one genetic-determinations were carried out. None of the patients presented a high-risk genotype for the TPMT gene. One of the children showed a medium-risk genotype *1/*3B,*1/*3C, but after 3 months of treatment with 6-MP he has not shown toxicity. This patient also showed a wild-type genotype for the NUDT15 gene which could explain the absence of toxicity during the treatment. Another patient has shown a heterozygous genotype for the rs116855232 and rs554405994 (NUDT15 gene). This patient has not already received treatment with 6-MP so we cannot evaluate the mutation influence yet.
Conclusion Althought we have not found patients with high-risk polymorphisms in TPMT yet, we support the implementation of this screening because the presence of this genotypes is related to severe toxicity and even death-risk in these patients.
We also have completed the procedure with the determination of mutations in the NUDT15 gene, increasing the probability of identifying patients with low tolerance to 6-MP.
To our knowledge, the present study is the first to evaluate the effect of polymorphisms in both TPMT and NUDT15 in the treatment with 6-MP, so definitive results could cidentify how those polymorphisms affect the toxicity related to 6-MP.
References and/or Acknowledgements 1. Ramos-Díaz. 2015May;75(5):1095–8.
2. Kotur, et al. 2015;16(15):1701–12.
No conflict of interest
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