The Role of TPMT, ITPA, and NUDT15 Variants during Mercaptopurine Treatment of Swedish Pediatric Patients with Acute Lymphoblastic Leukemia

NUDT15 polymorphism in healthy children with Bai nationality in Yunnan of China

“…Genotyping of NUDT15 , rather than TPMT , is strongly recommended to be detected in patients with Crohn's disease before initiating thiopurine drugs 12 . The association of NUDT15 polymorphism with thiopurine intolerance and myelotoxicity has largely been reported in pediatric patients with ALL 13–40 (Table 1). Interestingly, the NUDT15 variation is rarely found in European and African populations as compared with Asian populations, suggesting variability of the NUDT15 gene across different ethnic populations 22 .…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“…NUDT15 dephosphorylates thiopurine active metabolites and reduces the formation of active 6TG nucleotides, whereas ITPA is assumed to stimulate the formation of 6TG nucleotides. Results with respect to the influence of ITPA polymorphism in relation to myelosuppression, hepatotoxicity or TGN formation have not been consistent and its clinical relevance is still controversial ( Gerbek et al., 2018 ; Milosevic et al., 2018 ; Soler et al., 2018 ; Zhou et al., 2018 ; Khera et al., 2019 ; Wahlund et al., 2020 ). In contrast, in many recent studies, NUDT15 gene defects (rs116855232, rs186364861, rs869320766, rs201094029) have shown to result in increased TG availability for incorporation into DNA and have consistently been associated with TG toxicity including early myelosuppression ( Chiengthong et al., 2016 ; Moriyama et al., 2016 ; Lee and Yang, 2017 ; Moriyama et al., 2017 ; Moriyama et al., 2017 ; Soler et al., 2018 ; Choi et al., 2019 ; Khera et al., 2019 ; Koutsilieri et al., 2019 ).…”

Pharmacogenetic studies of thiopurine methyltransferase genotype‐phenotype concordance and effect of methotrexate on thiopurine metabolism

“…In contrast to TPMT, NUDT15 polymorphisms are more common in East Asian populations (allele frequency 10%) than in Caucasians (0.2-2%). 12,71,72 Recently, variations in the CRIM1 gene have been described to be an additional predictive factor for thiopurine toxicity. 73 Recently, methods to measure the levels of DNAincorporated TGN in WBC have been reported.…”

“…Recently, the impact of NUDT15 function in thiopurine metabolism and cytotoxicity was described and NUDT15 testing is currently being implemented in thiopurine treatment of childhood ALL. In contrast to TPMT, NUDT15 polymorphisms are more common in East Asian populations (allele frequency 10%) than in Caucasians (0.2‐2%) 12,71,72 . Recently, variations in the CRIM1 gene have been described to be an additional predictive factor for thiopurine toxicity 73 …”