NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia

Research output: Contribution to journalJournal article – Annual report year: 2018Researchpeer-review

  • Author: Tulstrup, Morten

    University of Copenhagen, Denmark

  • Author: Grosjean, Marie

    Department of Bio and Health Informatics, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Nielsen, Stine Nygaard

    Copenhagen University Hospital, Denmark

  • Author: Grell, Kathrine

    University of Copenhagen, Denmark

  • Author: Wolthers, Benjamin Ole

    University of Copenhagen, Denmark

  • Author: Wegener, Peder Skov

    University of Southern Denmark, Denmark

  • Author: Jonsson, Olafur Gisli

    Landspitali University Hospital, Iceland

  • Author: Lund, Bendik

    Norwegian University of Science and Technology, Norway

  • Author: Harila-Saari, Arja

    Uppsala University, Sweden

  • Author: Abrahamsson, Jonas

    University of Gothenburg, Sweden

  • Author: Vaitkeviciene, Goda

    Vilnius University, Lithuania

  • Author: Pruunsild, Kaie

    Talinn Children’s Hospital, Estonia

  • Author: Toft, Nina

    University of Copenhagen, Denmark

  • Author: Holm, Mette

    Aarhus University, Denmark

  • Author: Hulegårdh, Erik

    University of Gothenburg

  • Author: Liestøl, Sigurd

    University of Oslo

  • Author: Griskevicius, Laimonas

    Vilnius University

  • Author: Punab, Mari

    University of Tartu, Estonia

  • Author: Wang, Jinhua

    University of Minnesota, United States

  • Author: Carroll, William L.

    New York University, United States

  • Author: Zhang, Zeyu

    Technical University of Denmark, Denmark

  • Author: Dalgaard, Marlene D.

    Department of Bio and Health Informatics, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Gupta, Ramneek

    Disease Intelligence and Molecular Evolution, Department of Bio and Health Informatics, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Nersting, Jacob

    University of Copenhagen, Denmark

  • Author: Schmiegelow, Kjeld

    University of Copenhagen, Denmark

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The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means (wm) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation (wmDNA-TG/wmEry-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P = 2.09 × 10−10, minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy (P = 8.4 × 10−6 and 1.3 × 10−3, respectively). The association was mostly driven by differences in wmEry-TGN, but in regression analyses adjusted for wmEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher wmDNA-TG (P = 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or wmEry-TGN/wmDNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.

Original languageEnglish
JournalLeukemia
Volume32
Pages (from-to)2527-2535
ISSN0887-6924
DOIs
Publication statusPublished - 2018
CitationsWeb of Science® Times Cited: No match on DOI

ID: 154548962