title: Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age.
abstract: The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.
authors.affiliation: Department of Child Health, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Fukushima
authors.affiliation: Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Hosaka
authors.affiliation: Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan.
authors.forename: Yuni
authors.initials: Y
authors.lastname: Yamaki
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Kobayashi
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sakai
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Imagawa
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwabuchi
authors.affiliation: Department of Hematology and Oncology, Ibaraki Children's Hospital, Ibaraki, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Hematology and Oncology, Ibaraki Children's Hospital, Ibaraki, Japan.
authors.forename: Tomohei
authors.initials: T
authors.lastname: Nakao
authors.affiliation: Department of Hematology and Oncology, Ibaraki Children's Hospital, Ibaraki, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Hematology and Oncology, Ibaraki Children's Hospital, Ibaraki, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuchida
authors.affiliation: Department of Paediatric Haematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kiyokawa
authors.affiliation: Department of Hematology and Oncology, Ibaraki Children's Hospital, Ibaraki, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Koike
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Noguchi
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Sumazaki
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage*; D008780:Methyltransferases / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D000096964:Nudix Hydrolases; D000097630:Inosine Triphosphatase
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase