title: Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia.
abstract: OBJECTIVE
  Asparaginase (ASNase) is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia (ALL), but it is also associated with several toxicities.
  
  
  METHODS
  We recently reported the results of an association study between ASNase pathway genes and event-free survival (EFS) in childhood patients with ALL. The same polymorphisms were interrogated here in relation to allergies, pancreatitis, and thrombotic events following treatment with E. coli ASNase.
  
  
  RESULTS
  Among patients of the discovery group, allergies, and pancreatitis were more frequent in individuals who are homozygous for the triple-repeat allele (3R) of the asparagine synthetase (ASNS) gene, resulting in remarkably higher risk of these toxicities associated with 3R3R genotype [OR for allergies, 14.6; 95% confidence interval (CI), 3.6-58.7; P < 0.0005 and OR for pancreatitis, 8.6; 95% CI, 2.0-37.3; P = 0.01]. In contrast, the ASNS haplotype *1 harboring double-repeat (2R) allele had protective effect against these adverse reactions (P ≤ 0.01). The same haplotype was previously reported to confer reduction in EFS. The risk effect of 3R3R genotype was not replicated in the validation cohort, whereas the protective effect of haplotype *1 against allergies was maintained (P ≤ 0.002). Analysis with additional polymorphisms in ASNS locus in lymphoblastoid cell lines showed that haplotype *1 is diversified in several subtypes of which one was associated with reduced in vitro sensitivity to ASNase (rs10486009, P = 0.01) possibly explaining an association seen in clinical setting.
  
  
  CONCLUSIONS
  This finding might have implication for treatment individualization in ALL and other cancers using asparagine depletion strategies. Clin Cancer Res; 21(2); 329-34. ©2014 AACR. See related commentary by Avramis, p. 230.
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ben Tanfous
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of.
authors.forename: Bahram
authors.initials: B
authors.lastname: Sharif-Askari
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ceppi
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of.
authors.forename: Haithem
authors.initials: H
authors.lastname: Laaribi
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gagné
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of.
authors.forename: Julie
authors.initials: J
authors.lastname: Rousseau
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Labuda
authors.affiliation: Pediatric Oncology; Division of Hematology/Oncology, Children's Hospital; and.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: Pediatric Oncology; Division of Hematology/Oncology, Children's Hospital; and.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute; and.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of Pediatrics;
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of Pediatrics;
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdière
authors.affiliation: Research Center, CHU Sainte-Justine; Departments of Pediatrics; Pharmacology, University of Montreal, Montreal, Qubec, Canada; Departments of maja.krajinovic@umontreal.ca.
authors.forename: Maja
authors.initials: M
authors.lastname: Krajinovic
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001215:Asparaginase / Q000009:adverse effects* / Q000627:therapeutic use; D001217:Aspartate-Ammonia Ligase / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D000970:Antineoplastic Agents; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase