NUDT15 and TPMT genetic polymorphisms are related to 6‐mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon

Zgheib, Nathalie K.; Akika, Reem; Mahfouz, Rami; Aridi, Carol; Ghanem, Khaled M.; Saab, Raya; Abboud, Miguel R.; Tarek, Nidale; Solh, Hassan El; Muwakkit, Samar

doi:10.1002/pbc.26189

Cited by 41 publications

(30 citation statements)

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“…In particular, the NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ethnic differences in 6-MP tolerance [ 14 ]. The incidence of severe myelotoxicity was more frequent in patients with NUDT15 CT or TT genotype, when receiving standard-dose 6-MP therapy, as replicated by other studies [ 21 , 25 – 27 ]. These results indicate potentially clinical implications of NUDT15 genotyping and comprehensive pharmacogenetic models integrating NUDT15 variants to individualize 6-MP therapy.…”

Section: Introductionsupporting

confidence: 71%

“…The allele frequency of NUDT15 in Chinese children with ALL was 15.7%, which was slightly higher than that found in IBD patients (12.1%) [ 34 ] and Taiwan Chinese children with ALL (11.6%) [ 25 , 35 ] in previous studies. Conversely, the NUDT15 risk allele is less common in other populations, with prevalence of 2% in an admixed American population [ 24 ], 0.4% in Lebanese [ 27 ] and 8.8% in Uruguayan [ 33 ]. In contrast to NUDT15, the overall risk allele frequency of TPMT 719A > G was 2.9% in our population.…”

Section: Discussionmentioning

confidence: 99%

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Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?

Zhou

Yang

et al. 2018

BMC Cancer

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Background6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients.MethodsA total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C > T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated.ResultsThe minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377–9.501, P = 0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764–33.514, P = 3.75 × 10− 4). No differences were found between 6-MP dose intensity and ITPA polymorphisms.ConclusionNUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy.

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Section: Introductionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?

Zhou

Yang

et al. 2018

BMC Cancer

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“…Importantly, many investigators have been able to replicate these results in studies of thiopurine-treated patients with IBD or ALL 789101112131415161718. In the current study, we successfully established a significant association between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss.…”

Section: Discussionsupporting

confidence: 56%

“…The high specificity and sensitivity (89.4% and 93.2%, respectively) of NUDT15 p.Arg139Cys recorded by these authors indicate that this variant, rather than TPMT polymorphisms, may be an effective genetic marker for predicting thiopurine-induced adverse events, at least in East Asian populations. To date, this strong association has been confirmed in numerous studies involving subjects with IBD or ALL 789101112131415161718. In addition, a further investigation identified 4 NUDT15 coding variants, including p.Arg139Cys, that influence both nucleotide diphosphatase activity and levels of thiopurine active metabolites, and found loss-of-function NUDT15 variants to be associated with thiopurine intolerance 13.…”

Section: Introductionmentioning

confidence: 74%

NUDT15,FTO, andRUNX1genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

et al. 2017

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Background/AimsRecent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD).MethodsOne hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing.ResultsNone of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined.ConclusionsOf the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.

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“…[ 20 – 23 ] Besides, other studies in children with acute lymphoblastic leukemia (ALL) have recognized that the NUDT15 R139C variant increased the risk of developing thiopurine-induced toxicity ( P < .00001) and identified a variant in NUDT15 R139C gene to be associated with intolerance of thiopurine dose. [ 17 , 24 – 26 ] Suzuki et al [ 27 ] found that NUDT15 R139C genotyping could be beneficial in estimating the tolerated dose of 6-MP for Japanese patients with childhood ALL, particularly during the preschool age (younger than 7 years) ( P = .04). Furthermore, the variant frequency of NUDT15 R139C showed ethnic variability: 9.8% in East Asians, 4.1% in Hispanics, 0.2% in Europeans, and 0.0% in Africans.…”

Section: Literature Review and Discussionmentioning

confidence: 99%

NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects

et al. 2018

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Introduction:Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT∗3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics.Case presentation:A 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered.Conclusion:In this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT∗3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity.

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NUDT15 and TPMT genetic polymorphisms are related to 6‐mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon

Abstract: This is the first report on the association of TPMT and NUDT15 polymorphisms with MP dose intolerance in Arab patients with ALL. Genotyping for additional polymorphisms may be warranted for potential gene/allele-dose effect.

Cited by 41 publications

References 20 publications

Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?

Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?

NUDT15,FTO, andRUNX1genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects

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