Journal
GENETICS IN MEDICINE
Volume 21, Issue 9, Pages 2145-2150Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41436-019-0448-7
Keywords
NUDT15; TPMT; pharmacogenetics; adverse drug reaction; hematotoxicity
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Funding
- Robert Bosch Stiftung Stuttgart [U-PGx 668353]
- ICEPHA Graduate School Tubingen-Stuttgart
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Purpose: Severe hematotoxicity in patients with thiopurine therapy has been associated with genetic polymorphisms in the thiopurine S-methyltransferase (TPMT). While TPMT genetic testing is clinically implemented for dose individualization, alterations in the nudix hydrolase 15 (NUDT15) emerged as independent determinant of thiopurine-related hematotoxicity. Because data for European patients are limited, we investigated the relevance of NUDT15 in Europeans. Methods: Additionally to TPMT phenotyping/genotyping, we performed in-depth Sanger sequencing analyses of NUDT15 coding region in 107 European patients who developed severe thiopurine-related hematotoxicity as extreme phenotype. Moreover, genotyping for NUDT15 variants in 689 acute lymphoblastic leukemia (ALL) patients was performed. Results: As expected TPMT was the main cause of severe hematotoxicity in 31% of patients, who were either TPMT deficient (10%) or heterozygous carriers of TPMT variants (21%). By comparison, NUDT15 genetic polymorphism was identified in 14 (13%) patients including one novel variant (p.Metllle). Six percent of patients with severe toxicity carried variants in both TPMT and NUDT15. Among patients who developed toxicity within 3 months of treatment, 13% were found to be carriers of NUDT15 variants. Conclusion: Taken together, NUDT15 and TPMT genetics explain similar to 50% of severe thiopurine-related hematotoxicity, providing a compelling rationale for additional preemptive testing of NUDT15 genetics not only in Asians, but also in Europeans.
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