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Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008.
- Source :
-
British journal of haematology [Br J Haematol] 2019 Feb; Vol. 184 (3), pp. 405-417. Date of Electronic Publication: 2018 Nov 18. - Publication Year :
- 2019
-
Abstract
- Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10 <superscript>-8</superscript> ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10 <superscript>-6</superscript> ) and TAP2 (P = 1·59 × 10 <superscript>-5</superscript> ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.<br /> (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 3 genetics
Adolescent
Asparaginase administration & dosage
Child
Child, Preschool
Chromosomes, Human, Pair 19 genetics
Chromosomes, Human, Pair 6 genetics
Female
Genome-Wide Association Study
HLA-DQ Antigens genetics
Humans
Infant
Male
Polyethylene Glycols administration & dosage
Transcription Factors genetics
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Drug Hypersensitivity genetics
Genetic Predisposition to Disease
Genetic Variation
Neoplasm Proteins genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2141
- Volume :
- 184
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 30450575
- Full Text :
- https://doi.org/10.1111/bjh.15660