Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008

Research output: Contribution to journalJournal article – Annual report year: 2019Researchpeer-review

DOI

  • Author: Højfeldt, Sofie G.

    Aarhus University Hospital, Denmark

  • Author: Wolthers, Benjamin Ole

    Righospitalet , Denmark

  • Author: Tulstrup, Morten

    Righospitalet , Denmark

  • Author: Abrahamsson, Jonas

    University of Gothenburg, Sweden

  • Author: Gupta, Ramneek

    Disease Data Intelligence, Bioinformatics, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Harila-Saari, Arja

    Uppsala University, Sweden

  • Author: Heyman, Mats

    Karolinska Institutet, Sweden

  • Author: Henriksen, Louise T.

    Aarhus University Hospital, Denmark

  • Author: Jonsson, Olafur G.

    Landspitali University Hospital, Iceland

  • Author: Lähteenmäki, Päivi M.

    University of Turku, Finland

  • Author: Lund, Bendik

    St Olavs University Hospital, Norway

  • Author: Pruunsild, Kaie

    University Children’s Hospital Tallinn, Estonia

  • Author: Vaitkeviciene, Goda

    Vilnius University, Lithuania

  • Author: Schmiegelow, Kjeld

    Righospitalet , Denmark

  • Author: Albertsen, Birgitte K.

    Aarhus University Hospital, Denmark

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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 × 10-8). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). 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.
Original languageEnglish
JournalBritish Journal of Haematology
Volume184
Issue number3
Pages (from-to)405-417
Number of pages13
ISSN0007-1048
DOIs
Publication statusPublished - 2019
CitationsWeb of Science® Times Cited: No match on DOI

    Research areas

  • PEG-asparaginase, Genome-wide association study, Hypersensitivity, Paediatric acute lymphoblastic leukaemia

ID: 160859568