Combination of common and novel rare NUDT15 variants improves predictive sensitivity of thiopurine-induced leukopenia in children with acute lymphoblastic leukemia

Abstract

. Combination of common and novel rare NUDT15 variants improves predictive sensitivity of thiopurine-induced leukopenia in children with acute lymphoblastic leukemia.

Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil

“…The international population databases show that the frequency of the mutations that reduce the functional activity of the enzyme, such as those described by the PharmVar Consortium, exceeds 1% only in Asians, Latin American and Amerindian populations [14,15,25]. The most frequent mutations of these groups include the rs116855232 variant, either in isolation or combined with rs1272632214.…”

Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update

“…Therefore, genotype‐guided prescribing recommendations apply primarily to starting doses; subsequent dosing adjustments should be made based on close monitoring of clinical myelosuppression (or disease‐specific guidelines). In contrast, a full dose of mercaptopurine poses a severe risk of prolonged hematopoietic toxicity in NUDT15 poor metabolizers and pre‐emptive dose reductions are strongly recommended …”

“…In contrast, a full dose of mercaptopurine poses a severe risk of prolonged hematopoietic toxicity in NUDT15 poor metabolizers and pre-emptive dose reductions are strongly recommended. 32,33 The NUDT15 poor metabolizer phenotype is observed at a frequency of about 1 in every 50 patients of East Asian descent, which is more common than the TPMT poor metabolizer phenotype in Europeans, and, thus, genotyping NUDT15 in the Asian populations may be of particular clinical importance. NUDT15 deficiency is also more prevalent in individuals of Hispanic ethnicity, particularly those with high levels of Native American genetic ancestry.…”

Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia

“…With the development of genomic technology, novel and an ethnic-specific pharmacogenetic marker in NUDT15 (i.e., rs116855232) has been identified through genome-wide association studies (Yang et al, 2015;Moriyama et al, 2016) and validated by multiple independent studies. Allele frequency of rs116855232 is approximately 10% in East Asians, accounting for a large proportion of 6MP-induced leukopenia, as well as 6MP tolerance with high sensitivity and specificity in such population (Yin et al, 2017;Zhu et al, 2018;Relling et al, 2019;Schaeffeler et al, 2019). Ethnic specificity is observed for rs116855232, because allele of this variant is close to 0% in Caucasians and Africans, which is much lower than that in East Asians.…”

“…Ethnic specificity is observed for rs116855232, because allele of this variant is close to 0% in Caucasians and Africans, which is much lower than that in East Asians. After screening the whole coding region of NUDT15 in patients, less frequent and rare variants in NUDT15 were also identified to be related to 6MP-induced leukopenia, also exhibiting ethnic-specific manner (Moriyama et al, 2017;Zhu et al, 2018). Mechanically, TPMT can anabolize 6MP into the inactive methyl-mercaptopurine (Mcleod et al, 2000), whereas NUDT15 acts as a nucleotide triphosphate diphosphatase, catalyzing the hydrolysis of nucleoside triphosphates, including dGTP and its analogs (e.g., 6MP) (Moriyama et al, 2016).…”