title: Inosine triphosphate pyrophosphohydrolase (ITPA) polymorphic sequence variants in Chinese ALL children and possible association with mercaptopurine related toxicity.
abstract: Genetic polymorphisms are important factors in effects and toxicity of chemotherapeutics. This study aimed to investigate whether there was a correlation between genotype or haplotype of inosine triphosph pyrophosphohydrolase(ITPA) and toxicities during maintenance therapy with mercaptopurine (6-MP) in Chinese patients with acute lymphoblastic leukemia (ALL). 95 ALL children who hospitalized between October 2004 and September 2007,were retrospectively analyzed. 6-MP toxicity was documented according to Common Toxicity Criteria, Version 2.0. ITPA sequencing was undertaken. Correlation between genotype/haplotype and 6-MP toxicity was analyzed. The results indicated that 50 cases (52.6%) had grade III-IV of bone marrow inhibition. These children had long-term disease-free survival (DFS), without hepatic and other organs' dysfunction and secondary tumors. Three variations were observed in ITPA exon 2 (94 C → A), exon 3 (138 G → A), and exon 8 (561 G → A), the 94A carriers (CA and AA) had a lower risk of developing 6-MP toxicity when compared with carriers of the CC genotype (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.12-0.98, P = 0.039). The risk of 6-MP intolerance was decreased in patients with 138 allele and 561 allele polymorphism, but with no significant difference. Patients carrying the haplotype 94A-138A-561A was tolerance compared to those with wild-type haplotype 94C-138G-561G (OR: 0.26, 95% CI 0.07-0.94 P = 0.043). In conclusion, the risk of 6-MP intolerance was decreased in patients with 138 allele and 561 allele polymorphism, but without significant difference. Patients carrying the haplotype 94A-138A-561A was tolerance compared to those with the wild-type haplotype 94C-138G-561G.
authors.affiliation: Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University Beijing 100045, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ma
authors.affiliation: Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University Beijing 100045, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University Beijing 100045, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Jin
authors.affiliation: Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University Beijing 100045, China.
authors.forename: Weijing
authors.initials: W
authors.lastname: Li
authors.affiliation: Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University Beijing 100045, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University Beijing 100045, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University Beijing 100045, China.
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University Beijing 100045, China.
authors.forename: Xingjun
authors.initials: X
authors.lastname: Li
authors.affiliation: Beijing Daopei Hospital Beijing 100049, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Xie
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D012189:Retrospective Studies; D000097630:Inosine Triphosphatase
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D011755:Pyrophosphatases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase
keywords: ALL children; ITPA; mercaptopurine related toxicity