Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age

Suzuki, Hisato; Fukushima, Hiroko; Suzuki, Ryoko; Hosaka, Sho; Yamaki, Yuni; Kobayashi, Chie; Sakai, Aiko; Imagawa, Kazuo; Iwabuchi, Akira; Yoshimi, Ai; Nakao, Tomohei; Kato, Keisuke; Tsuchida, Masahiro; Kiyokawa, Nobutaka; Koike, Kenichi; Noguchi, Emiko; Fukushima, Takashi; Sumazaki, Ryo

doi:10.1038/jhg.2016.55

Cited by 26 publications

(23 citation statements)

References 23 publications

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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%

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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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Section: Discussionsupporting

confidence: 56%

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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“…normal) for TPMT still develop toxicity that necessitates MP dose reduction or protocol interruption . Recently, several studies reported on an inherited nucleoside diphosphate‐linked moiety X motif 15 ( NUDT15 ) c.415C>T (rs116855232) nonsynonymous (R139C) low‐function variant that is associated with decreased thiopurine metabolism and leukopenia in ALL and other diseases . This allele and a few others in the same gene are most common among individuals of Asian ancestry, with the initial susceptibility to thiopurine‐related leucopenia being reported in a cohort of Korean subjects with Crohn disease .…”

Section: Introductionmentioning

confidence: 99%

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

Akika

Mahfouz

et al. 2016

Pediatric Blood & Cancer

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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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Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age

Cited by 26 publications

References 23 publications

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

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

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

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

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