Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia
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 NUD...
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doaj-92e9c8edba0a4969987f0382d7d6b6c72020-11-25T02:25:12ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-03-011110.3389/fphar.2020.00267514455Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic LeukemiaMinyuan Cao0Minyuan Cao1Dandan Yin2Yun Qin3Fei Liao4Yali Su5Xuyang Xia6Ju Gao7Yiping Zhu8Wei Zhang9Yang Shu10Xiaoxi Lu11Department of Pediatric Hematology and Oncology, West China Second Hospital, Sichuan University, Chengdu, ChinaDepartment of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Radiology, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Pediatric Hematology and Oncology, West China Second Hospital, Sichuan University, Chengdu, ChinaDepartment of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Pediatric Hematology and Oncology, West China Second Hospital, Sichuan University, Chengdu, ChinaDepartment of Pediatric Hematology and Oncology, West China Second Hospital, Sichuan University, Chengdu, ChinaDepartment of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Laboratory Medicine, Precision Medicine Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Pediatric Hematology and Oncology, West China Second Hospital, Sichuan University, Chengdu, ChinaA 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 NUDT15wt/wtTPMTwt/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.https://www.frontiersin.org/article/10.3389/fphar.2020.00267/fullmercaptopurineleukopeniahepatoxicityadverse drug reactionpharmacogeneticsCYP2A7 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Minyuan Cao Minyuan Cao Dandan Yin Yun Qin Fei Liao Yali Su Xuyang Xia Ju Gao Yiping Zhu Wei Zhang Yang Shu Xiaoxi Lu |
spellingShingle |
Minyuan Cao Minyuan Cao Dandan Yin Yun Qin Fei Liao Yali Su Xuyang Xia Ju Gao Yiping Zhu Wei Zhang Yang Shu Xiaoxi Lu Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia Frontiers in Pharmacology mercaptopurine leukopenia hepatoxicity adverse drug reaction pharmacogenetics CYP2A7 |
author_facet |
Minyuan Cao Minyuan Cao Dandan Yin Yun Qin Fei Liao Yali Su Xuyang Xia Ju Gao Yiping Zhu Wei Zhang Yang Shu Xiaoxi Lu |
author_sort |
Minyuan Cao |
title |
Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia |
title_short |
Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia |
title_full |
Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia |
title_fullStr |
Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia |
title_full_unstemmed |
Screening of Novel Pharmacogenetic Candidates for Mercaptopurine-Induced Toxicity in Patients With Acute Lymphoblastic Leukemia |
title_sort |
screening of novel pharmacogenetic candidates for mercaptopurine-induced toxicity in patients with acute lymphoblastic leukemia |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2020-03-01 |
description |
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 NUDT15wt/wtTPMTwt/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. |
topic |
mercaptopurine leukopenia hepatoxicity adverse drug reaction pharmacogenetics CYP2A7 |
url |
https://www.frontiersin.org/article/10.3389/fphar.2020.00267/full |
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