Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia
Minyuan Cao, Dandan Yin, Yun Qin, Fei Liao, Yali Su, Xuyang Xia, Ju Gao, Yiping Zhu, Wei Zhang, Yang Shu, Xiaoxi Lu
Abstract
A small proportion of patients with acute lymphoblastic leukemia 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 suffered such adverse drug reaction have NUDT15wt/wtTPMTwt/wt genotype, indicating other genetic factors may take part in. In this study, we genotyped 539 exon-located non-silent pharmacogenetic variants in genes involved phase I/II of drug metabolism in 173 pediatric patients with acute lymphoblastic leukemia, and conducted association screening for 6MP-induced leucopenia. Besides NUDT15 (rs116855232, P = 6.4 × 10-11) and TPMT (rs1142345, P = 0.003), several novel variants were identified with the top signal located 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 6-MP induced hepatoxicity (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 validation with large sample size and investigation of related mechanisms are further needed.