uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008
Aarhus Univ Hosp, Child & Adolescent Hlth, Aarhus, Denmark.
Univ Hosp Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark.
Univ Hosp Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark.
Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Paediat, Gothenburg, Sweden.
Show others and affiliations
2019 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 184, no 3, p. 405-417Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 184, no 3, p. 405-417
Keywords [en]
PEG-asparaginase, genome-wide association study, hypersensitivity, paediatric acute lymphoblastic leukaemia
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-369681DOI: 10.1111/bjh.15660ISI: 000456167900012PubMedID: 30450575OAI: oai:DiVA.org:uu-369681DiVA, id: diva2:1271077
Available from: 2018-12-15 Created: 2018-12-15 Last updated: 2019-02-12Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Harila-Saari, Arja H.

Search in DiVA

By author/editor
Harila-Saari, Arja H.
By organisation
Neuropediatrics/Paediatric oncology
In the same journal
British Journal of Haematology
Pediatrics

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 144 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf