title: PACSIN2 polymorphism is associated with thiopurine-induced hematological toxicity in children with acute lymphoblastic leukaemia undergoing maintenance therapy.
abstract: Adequate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), with 6-mercaptopurine as an essential component, is necessary for retaining durable remission. Interruptions or discontinuations of the therapy due to drug-related toxicities, which can be life threatening, may result in an increased risk of relapse. In this retrospective study including 305 paediatric ALL patients undergoing maintenance therapy, we systematically investigated the individual and combined effects of genetic variants of folate pathway enzymes, as well as of polymorphisms in PACSIN2 and ITPA, on drug-induced toxicities by applying a multi-analytical approach including logistic regression (LR), classification and regression tree (CART) and generalized multifactor dimensionality reduction (GMDR). In addition to the TPMT genotype, confirmed to be a major determinant of drug related toxicities, we identified the PACSIN2 rs2413739TT genotype as being a significant risk factor for 6-MP-induced toxicity in wild-type TPMT patients. A gene-gene interaction between MTRR (rs1801394) and MTHFR (rs1801133) was detected by GMDR and proved to have an independent effect on the risk of stomatitis, as shown by LR analysis. To our knowledge, this is the first study showing PACSIN2 genotype association with hematological toxicity in ALL patients undergoing maintenance therapy.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Alenka
authors.initials: A
authors.lastname: Smid
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Natasa
authors.initials: N
authors.lastname: Karas-Kuzelicki
authors.affiliation: University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Jazbec
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Irena
authors.initials: I
authors.lastname: Mlinaric-Rascan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005287:Ferredoxin-NADP Reductase; D005492:Folic Acid; D015122:Mercaptopurine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D011755:Pyrophosphatases; C120714:PACSIN2 protein, human; C111241:methionine synthase reductase; C573423:MTHFR protein, human; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase