Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry

Abstract

Prolonged exposure to thiopurines (eg, mercaptopurine [MP]) is essential for curative therapy in acute lymphoblastic leukemia (ALL), but is also associated with frequent dose-limiting hematopoietic toxicities, which is partly explained by inherited genetic polymorphisms in drug metabolizing enzymes (eg, ). Recently, our group and others identified germ line genetic variants in as another major cause of thiopurine-related myelosuppression, particularly in Asian and Hispanic people. In this article, we describe 3 novel coding variants (p.R34T, p.K35E, and p.G17_V18del) in 5 children with ALL enrolled in frontline protocols in Singapore, Taiwan, and at St. Jude Children's Research Hospital. Patients carrying these variants experienced significant toxicity and reduced tolerance to MP across treatment protocols. Functionally, all 3 variants led to partial to complete loss of NUDT15 nucleotide diphosphatase activity and negatively influenced protein stability. In particular, the p.G17_V18del variant protein showed extremely low thermostability and was completely void of catalytic activity, thus likely to confer a high risk of thiopurine intolerance. This in-frame deletion was only seen in African and European patients, and is the first risk variant identified in non-Asian, non-Hispanic populations. In conclusion, we discovered 3 novel loss-of-function variants in associated with MP toxicity, enabling more comprehensive pharmacogenetics-based thiopurine dose adjustments across diverse populations.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

“…Sequence data for NUDT15 were examined for the presence of all coding variants either previously associated with TIM [8][9][10] or identified in gnomAD 25 and predicted as deleterious using the Protein Variation Effect Analyzer 26 (Table 2 and eFigure 5 in the Supplement). However, 4 (p.Lys33Glu, p.Val75Gly, p.Cys28GlyfsTer28, and p.Met1?)…”

“…6 However, TPMT variants are only found in 25% of patients of European ancestry affected by TIM, suggesting the presence of other genetic and environmental determinants. 6,7 Studies in patients of East Asian ancestry 8,9 and other populations [10][11][12][13][14] have identified variants in nudix hydrolase 15 (NUDT15; RefSeqGene NG_047021.1) as risk factors for TIM. Although a novel NUDT15 variant (rs746071566, p.Gly17_Val18del) was described by Moriyama et al 10 in a single pediatric patient of European ancestry affected by TIM, the association of the NUDT15 genetic variation with TIM in this population has not been fully evaluated.…”

An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana‐Farber Cancer Institute ALL Consortium protocol 05‐001

“…34 We 15,16 and others 20,[35][36][37][38][39][40] have previously described associations between functional genetic polymorphisms and TRT or survival among children with leukemia and the prevalence of some of these polymorphisms is known to differ between ethnic groups. 11,20,33,[41][42][43] In exploratory analyses, we targeted a small subset of polymorphisms that were relatively common (population prevalence of at least 10%) and that could potentially impact either TRT or survival. We observed significant differences between Hispanic and non-Hispanic patients in the prevalence of four of the 19 polymorphisms analyzed (Supplementary Table 3); however, the clinical import of these germline genetic differences remains unclear.…”

Massive parallel variant characterization identifiesNUDT15alleles associated with thiopurine toxicity

“…subjects in previously published datasets 20,21,31,44,45 . The ALL cohort included US Children's 31 .…”

“…The ALL cohort included US Children's 31 . TPMT risk variants (e.g., rs1800462) were also genotyped as previously reported 20,21,31,44,45 , and cases carrying TPMT variants were excluded from further analysis. This study was approved by the respective institutional review boards, and informed consent was obtained from the parents, guardians, and/or patients, as appropriate.…”