Meta-analysis of the association between NUDT15 gene polymorphism and 6-MP toxicity during chemotherapy in childhood acute lymphoblastic leukemia / 国际儿科学杂志

Objective:To evaluate systematically the association between the c. 415>C polymorphism of NUDT15 gene and the toxicity of 6-mercaptopurine(6-MP)in children with acute lymphoblastic leukemia(ALL).Methods:The literatures in domestic and foreign databases were retrieved: PubMed, EmBase, Cochrane Library, CNKI, CBM, VIP Chinese Sci-tech Journal Database, and Wanfang Database.The language was limited to Chinese or English.A case-control study or cohort study of 6-MP treatment in pediatric ALL related to the toxicity of the NUDT15 gene c. 415>C polymorphism was included.The time of search was set from the establishment of the database to October 1st, 2020.Two researchers screened the literature independently, extracted data from the literature that met the inclusion criteria, and evaluated the quality of the included studies.The association between locus polymorphism and toxicity during 6-MP chemotherapy was analyzed by Meta analysis with Rev Man 5.3 and Stata 12.0 software.Results:Nine studies were finally included, eight of which were cohort studies and one was a case-control study, with a total of 1 068 patients.The results showed that under the five genetic models, the mutation at c. 415>C of NUDT15 gene was significantly associated with the risk of leukopenia and neutropenia( P<0.01), while hepatotoxicity was with no significant association between the occurrence risk of damage( P>0.05). Conclusion:The mutation at c. 415>C of NUDT15 gene significantly increased the incidence of leukopenia and neutropenia during 6-MP chemotherapy, while there was no significant effect on the occurrence of hepatotoxicity.

Relationship between NUDT15 gene polymorphism and tolerance to treatment with 6-mercaptopurine in children with acute lymphoblastic leukemia / 白血病·淋巴瘤

Objective:To investigate the relationship between NUDT15 gene polymorphism and tolerance to treatment with 6-mercaptopurine (6-MP) in children with acute lymphoblastic leukemia (ALL).Methods:Fifty-eight children diagnosed with ALL in Shanxi Children's Hospital from January 2019 to December 2020 were recruited. All of them were treated with CCLG-ALL2018 chemotherapy regimen and the bone marrow showed complete remission. They received 6-MP oral treatment during maintenance treatment. Single nucleotide polymorphism of NUDT15 gene was detected by real-time fluorescence quantitative polymerase chain reaction. The bone marrow suppression after 6-MP treatment and 6-MP tolerance dose in patients with different NUDT15 genotypes were analyzed.Results:Among 58 patients, 3 patients had NUDT15 TT genotype, 46 patients had CC genotype and 9 patients had TC genotype. During maintenance treatment with 6-MP, the differences in leukocyte count, hemoglobin and platelet count among the three groups of patients with different NUDT15 genotypes were statistically significant (all P < 0.05). Among 58 patients, 23 (39.66%) patients had varying degrees of neutropenia after medication, including 16 cases of NUDT15 CC genotype, 5 cases of TC genotype and 2 cases of TT genotype. There was a statistically significant difference in bone marrow suppression among the three groups ( H = 29.10, P < 0.05). The dosages of 6-MP used in patients with TT, CC and TC genotypes were (10.4±8.8) mg·m -2·d -1, (41.5±1.3) mg·m -2·d -1 and (36.7±2.4) mg·m -2·d -1, respectively, and the difference was statistically significant ( F = 16.95, P < 0.05). Conclusions:Children with different NUDT15 genotypes have different tolerance to 6-MP, and NUDT15 gene polymorphism is associated with 6-MP intolerance during maintenance treatment in children with ALL, which may affect the treatment of the disease.

APEX1 Polymorphism and Mercaptopurine-Related Early Onset Neutropenia in Pediatric Acute Lymphoblastic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients. MATERIALS AND METHODS: Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients. RESULTS: Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01). CONCLUSION: We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia.

NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. RESULTS: A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. CONCLUSION: NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.

Azathioprine-induced myelosuppression in a pemphigus patient with a heterozygous mutation in the NUDT15 gene / 中华皮肤科杂志

A 49-year-old male patient presented with repeated oral erosions for 1 year,as well as cutaneous erythema and blisters for 1 month.According to histopathological examination and detection of specific antibodies of pemphigus,the patient was diagnosed with pemphigus vulgaris.After the treatment with oral prednisone and azathioprine for 1 month,the white blood cell count and segmented neutrophilic granulocyte count both decreased.After withdrawal of azathioprine,the patient was subcutaneously injected with 150 μg recombinant human granulocyte colony-stimulating factor for 1 session.Then,the white blood cell count became normal.Genotyping test revealed that the patient carried a heterozygous mutation in the NUDT15 gene (JZ274),and was homozygous for wild-type TPMT*2,TPMT*3C and ITPA genes.The patient was diagnosed with azathioprine-induced myelosuppression.

NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

BACKGROUND/AIMS: Recent 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). METHODS: One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. RESULTS: None 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. CONCLUSIONS: Of 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.