title: Pharmacogenetic analysis of pediatric patients with acute lymphoblastic leukemia: a possible association between survival rate and ITPA polymorphism.
abstract: Genetic polymorphisms are important factors in the effects and toxicity of chemotherapeutics. To analyze the pharmacogenetic and ethnic differences in chemotherapeutics, major genes implicated in the treatment of acute lymphoblastic leukemia (ALL) were analyzed. Eighteen loci of 16 genes in 100 patients with ALL were analyzed. The distribution of variant alleles were CYP3A4*1B (0%), CYP3A5*3 (0%), GSTM1 (21%), GSTP1 (21%), GSTT1 (16%), MDR1 exon 21 (77%), MDR1 exon 26 (61%), MTHFR 677 (63%), MTHFR 1298 (29%), NR3C1 1088 (0%), RFC1 80 (68%), TPMT combined genotype (7%), VDR intron 8 (11%), VDR FokI (83%), TYMS enhancer repeat (22%) and ITPA 94 (30%). The frequencies of single nucleotide polymorphisms (SNPs) of 10 loci were statistically different from those in Western Caucasians. Dose percents (actual/planned dose) or toxicity of mercaptopurine and methotrexate were not related to any SNPs. Event free survival (EFS) rate was lower in ITPA variants, and ITPA 94 AC/AA variant genotypes were the only independent risk factor for lower EFS in multivariate analysis, which was a different pharmacogenetic implication from Western studies. This study is the first pharmacogenetic study in Korean pediatric ALL. Our result suggests that there are other possible pharmacogenetic factors besides TPMT or ITPA polymorphisms which influence the metabolism of mercaptopurine in Asian populations.
authors.affiliation: Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hyery
authors.initials: H
authors.lastname: Kim
authors.forename: Hyoung Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Jang
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Kim
authors.forename: Yongtaek
authors.initials: Y
authors.lastname: Oh
authors.forename: Byoung-Don
authors.initials: BD
authors.lastname: Han
authors.forename: Ji-Yeob
authors.initials: JY
authors.lastname: Choi
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Kim
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Kyung Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Hyo Seop
authors.initials: HS
authors.lastname: Ahn
mesh_terms: D000293:Adolescent; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D008780:Methyltransferases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D011379:Prognosis; D011755:Pyrophosphatases / Q000235:genetics*; D000097630:Inosine Triphosphatase
chemical_list: D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase