Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia.

Abstract

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.

• Authors: Mohsen Ben Tanfous, Bahram Sharif-Askari, Francesco Ceppi, Haithem Laaribi, Vincent Gagné, Julie Rousseau, Malgorzata Labuda, Lewis B Silverman, Stephen E Sallan, Donna Neuberg, Jeffery L Kutok, Daniel Sinnett, Caroline Laverdière, Maja Krajinovic
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 2 Pg. 329-34 (Jan 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 24907114 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Asparaginase
• Aspartate-Ammonia Ligase

Topics

• Antineoplastic Agents (adverse effects, therapeutic use)
• Asparaginase (adverse effects, therapeutic use)
• Aspartate-Ammonia Ligase (genetics)
• Cell Line, Tumor
• Child
• Female
• Gene Frequency
• Genetic Association Studies
• Haplotypes
• Humans
• Male
• Polymorphism, Single Nucleotide
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, enzymology, genetics)
• Repetitive Sequences, Nucleic Acid