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

Morten Tulstrup, Marie Grosjean, Stine Nygaard Nielsen, Kathrine Grell, Benjamin Ole Wolthers, Peder Skov Wegener, Olafur Gisli Jonsson, Bendik Lund, Arja Harila-Saari, Jonas Abrahamsson, Goda Vaitkeviciene, Kaie Pruunsild, Nina Toft, Mette Holm, Erik Hulegårdh, Sigurd Liestøl, Laimonas Griskevicius, Mari Punab, Jinhua Wang, William L. CarrollZeyu Zhang, Marlene D. Dalgaard, Ramneek Gupta, Jacob Nersting, Kjeld Schmiegelow*

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    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

    Cite this

    Tulstrup, M., Grosjean, M., Nielsen, S. N., Grell, K., Wolthers, B. O., Wegener, P. S., ... Schmiegelow, K. (2018). NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia. Leukemia, 32, 2527-2535. https://doi.org/10.1038/s41375-018-0245-3
    Tulstrup, Morten ; Grosjean, Marie ; Nielsen, Stine Nygaard ; Grell, Kathrine ; Wolthers, Benjamin Ole ; Wegener, Peder Skov ; Jonsson, Olafur Gisli ; Lund, Bendik ; Harila-Saari, Arja ; Abrahamsson, Jonas ; Vaitkeviciene, Goda ; Pruunsild, Kaie ; Toft, Nina ; Holm, Mette ; Hulegårdh, Erik ; Liestøl, Sigurd ; Griskevicius, Laimonas ; Punab, Mari ; Wang, Jinhua ; Carroll, William L. ; Zhang, Zeyu ; Dalgaard, Marlene D. ; Gupta, Ramneek ; Nersting, Jacob ; Schmiegelow, Kjeld. / NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia. In: Leukemia. 2018 ; Vol. 32. pp. 2527-2535.
    @article{f535561319c04ca48cee7a5a72c1eb1b,
    title = "NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia",
    abstract = "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.",
    author = "Morten Tulstrup and Marie Grosjean and Nielsen, {Stine Nygaard} and Kathrine Grell and Wolthers, {Benjamin Ole} and Wegener, {Peder Skov} and Jonsson, {Olafur Gisli} and Bendik Lund and Arja Harila-Saari and Jonas Abrahamsson and Goda Vaitkeviciene and Kaie Pruunsild and Nina Toft and Mette Holm and Erik Huleg{\aa}rdh and Sigurd Liest{\o}l and Laimonas Griskevicius and Mari Punab and Jinhua Wang and Carroll, {William L.} and Zeyu Zhang and Dalgaard, {Marlene D.} and Ramneek Gupta and Jacob Nersting and Kjeld Schmiegelow",
    year = "2018",
    doi = "10.1038/s41375-018-0245-3",
    language = "English",
    volume = "32",
    pages = "2527--2535",
    journal = "Leukemia",
    issn = "0887-6924",
    publisher = "Nature Publishing Group",

    }

    Tulstrup, M, Grosjean, M, Nielsen, SN, Grell, K, Wolthers, BO, Wegener, PS, Jonsson, OG, Lund, B, Harila-Saari, A, Abrahamsson, J, Vaitkeviciene, G, Pruunsild, K, Toft, N, Holm, M, Hulegårdh, E, Liestøl, S, Griskevicius, L, Punab, M, Wang, J, Carroll, WL, Zhang, Z, Dalgaard, MD, Gupta, R, Nersting, J & Schmiegelow, K 2018, 'NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia', Leukemia, vol. 32, pp. 2527-2535. https://doi.org/10.1038/s41375-018-0245-3

    NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia. / Tulstrup, Morten; Grosjean, Marie; Nielsen, Stine Nygaard; Grell, Kathrine; Wolthers, Benjamin Ole; Wegener, Peder Skov; Jonsson, Olafur Gisli; Lund, Bendik; Harila-Saari, Arja; Abrahamsson, Jonas; Vaitkeviciene, Goda; Pruunsild, Kaie; Toft, Nina; Holm, Mette; Hulegårdh, Erik; Liestøl, Sigurd; Griskevicius, Laimonas; Punab, Mari; Wang, Jinhua; Carroll, William L.; Zhang, Zeyu; Dalgaard, Marlene D.; Gupta, Ramneek; Nersting, Jacob; Schmiegelow, Kjeld.

    In: Leukemia, Vol. 32, 2018, p. 2527-2535.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia

    AU - Tulstrup, Morten

    AU - Grosjean, Marie

    AU - Nielsen, Stine Nygaard

    AU - Grell, Kathrine

    AU - Wolthers, Benjamin Ole

    AU - Wegener, Peder Skov

    AU - Jonsson, Olafur Gisli

    AU - Lund, Bendik

    AU - Harila-Saari, Arja

    AU - Abrahamsson, Jonas

    AU - Vaitkeviciene, Goda

    AU - Pruunsild, Kaie

    AU - Toft, Nina

    AU - Holm, Mette

    AU - Hulegårdh, Erik

    AU - Liestøl, Sigurd

    AU - Griskevicius, Laimonas

    AU - Punab, Mari

    AU - Wang, Jinhua

    AU - Carroll, William L.

    AU - Zhang, Zeyu

    AU - Dalgaard, Marlene D.

    AU - Gupta, Ramneek

    AU - Nersting, Jacob

    AU - Schmiegelow, Kjeld

    PY - 2018

    Y1 - 2018

    N2 - 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.

    AB - 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.

    U2 - 10.1038/s41375-018-0245-3

    DO - 10.1038/s41375-018-0245-3

    M3 - Journal article

    C2 - 30201983

    AN - SCOPUS:85053065749

    VL - 32

    SP - 2527

    EP - 2535

    JO - Leukemia

    JF - Leukemia

    SN - 0887-6924

    ER -