Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia.
| Autor: | Ben Tanfous M; Research Center, CHU Sainte-Justine; Departments of., Sharif-Askari B; Research Center, CHU Sainte-Justine; Departments of., Ceppi F; Research Center, CHU Sainte-Justine; Departments of., Laaribi H; Research Center, CHU Sainte-Justine; Departments of., Gagné V; Research Center, CHU Sainte-Justine; Departments of., Rousseau J; Research Center, CHU Sainte-Justine; Departments of., Labuda M; Research Center, CHU Sainte-Justine; Departments of., Silverman LB; Pediatric Oncology; Division of Hematology/Oncology, Children's Hospital; and., Sallan SE; Pediatric Oncology; Division of Hematology/Oncology, Children's Hospital; and., Neuberg D; Biostatistics and Computational Biology, Dana-Farber Cancer Institute; and., Kutok JL; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Sinnett D; Research Center, CHU Sainte-Justine; Departments of Pediatrics;, Laverdière C; Research Center, CHU Sainte-Justine; Departments of Pediatrics;, Krajinovic M; Research Center, CHU Sainte-Justine; Departments of Pediatrics; Pharmacology, University of Montreal, Montreal, Qubec, Canada; Departments of maja.krajinovic@umontreal.ca. |
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| Jazyk: | angličtina |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Jan 15; Vol. 21 (2), pp. 329-34. Date of Electronic Publication: 2014 Jun 06. |
| DOI: | 10.1158/1078-0432.CCR-14-0508 |
| Abstrakt: | Purpose: 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. Experimental Design: 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. (©2014 American Association for Cancer Research.) |
| Databáze: | MEDLINE |
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