AUTHOR=Cao Minyuan , Yin Dandan , Qin Yun , Liao Fei , Su Yali , Xia Xuyang , Gao Ju , Zhu Yiping , Zhang Wei , Shu Yang , Lu Xiaoxi 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00267

DOI=10.3389/fphar.2020.00267

ISSN=1663-9812

ABSTRACT=<p>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 <italic>TPMT</italic> and <italic>NUDT15</italic>. However, a minority of patients who suffered such adverse drug reaction have <italic>NUDT15</italic><sup>wt/wt</sup><italic>TPMT</italic><sup>wt/wt</sup> 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 <italic>NUDT15</italic> (rs116855232, <italic>P</italic> = 6.4 × 10<sup>−11</sup>) and <italic>TPMT</italic> (rs1142345, <italic>P</italic> = 0.003), a novel variant was identified in <italic>CYP2A7</italic> gene (i.e., rs73032311, <italic>P</italic> = 0.0007), which is independent of <italic>NUDT15/TPMT</italic> variant. In addition, a variant (i.e., rs4680) in COMT is significantly associated with 6MP-induced hepatotoxicity (<italic>P</italic> = 0.007). In conclusion, variants in <italic>CYP2A7</italic> and <italic>COMT</italic> 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.</p>