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


ABSTRACT: A small proportion of patients with acute lymphoblastic leukemia (ALL) may experience severe leukopenia after treating with 6-mercaptopurine (6MP), which can be largely explained by germline variants in TPMT and NUDT15. However, a minority of patients who suffered such adverse drug reaction have NUDT15 wt/wt TPMT wt/wt genotype, indicating that other genetic factors may take part in. In this study, we genotyped 539 exon-located nonsilent pharmacogenetic variants in genes involved in phase I/II of drug metabolism in 173 pediatric patients with ALL and conducted association screening for 6MP-induced leukopenia. Besides NUDT15 (rs116855232, P = 6.4 × 10-11) and TPMT (rs1142345, P = 0.003), a novel variant was identified in CYP2A7 gene (i.e., rs73032311, P = 0.0007), which is independent of NUDT15/TPMT variant. In addition, a variant (i.e., rs4680) in COMT is significantly associated with 6MP-induced hepatotoxicity (P = 0.007). In conclusion, variants in CYP2A7 and COMT may be considered as novel potential pharmacogenetic markers for 6MP-induced toxicities, but additional independent validations with large sample size and investigations on related mechanisms are further needed.

SUBMITTER: Cao M 

PROVIDER: S-EPMC7098961 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Cao Minyuan M   Yin Dandan D   Qin Yun Y   Liao Fei F   Su Yali Y   Xia Xuyang X   Gao Ju J   Zhu Yiping Y   Zhang Wei W   Shu Yang Y   Lu Xiaoxi X  

Frontiers in pharmacology 20200320


A small proportion of patients with acute lymphoblastic leukemia (ALL) may experience severe leukopenia after treating with 6-mercaptopurine (6MP), which can be largely explained by germline variants in <i>TPMT</i> and <i>NUDT15</i>. However, a minority of patients who suffered such adverse drug reaction have <i>NUDT15</i> <sup>wt/wt</sup> <i>TPMT</i> <sup>wt/wt</sup> genotype, indicating that other genetic factors may take part in. In this study, we genotyped 539 exon-located nonsilent pharmaco  ...[more]

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